longer after VenObi therapy compared to ClbObi therapy (median
1225 days versus 227 days, p <2e16)(Fig D).
Based on a covariate screening of 28 biological and clinical features,
the final model showed a significant impact on MRD growth dynamics
by VenObi treatment, high MRD levels at the start of treatment,
high CLLIPI, del11q, higher disease burden, response to treatment,
and IGHV status (Fig E,F).
Conclusion: This analysis establishes a robust, populationbased
model of MRD growth dynamics that allows description of growth
trajectories and treatment effects after treatment cessation. In
addition to more effective MRD eradication with VenObi, our
results demonstrate that MRD growth is modulated more efficiently
by BCL2targeting treatment in contrast to genotoxic
chemoimmunotherapy.
The research was funded by: HoffmannLa Roche Ltd.; AbbVie Inc.
Keywords: Diagnostic and Prognostic Biomarkers, Chronic Lympho-
cytic Leukemia (CLL)
Conflicts of interests pertinent to the abstract
O. AlSawaf
Consultant or advisory role: Roche, Abbvie
Honoraria: Roche, Abbvie
Research funding: Roche, Abbvie
Educational grants: Roche, Abbvie
T. Lu
Employment or leadership position: Genentec Inc.
M. Z. Liao
Employment or leadership position: Genentec Inc.
A. Panchal
Employment or leadership position: Roche Products Ltd.
T. Ching
Employment or leadership position: Adaptive Biotechnologies Corp.
A.M. Fink
Honoraria: Celgene, Janssen, HoffmannLaRoche
E. Tausch
Honoraria: Roche AG, AbbVie
M. Ritgen
Honoraria: HoffmannLaRoche, AbbVie
Research funding: HoffmannLaRoche
K.A. Kreuzer
Honoraria: Roche, AbbVie
Research funding: Roche, AbbVie
S. Kim
Employment or leadership position: AbbVie Inc.
D. Miles
Employment or leadership position: Genentec Inc.
C. Wendtner
Honoraria: HoffmannLaRoche, AbbVie, JanssenCilag, Gilead,
MorphoSys
S. Stilgenbauer
Honoraria: AbbVie, AstraZeneca, Celgene, Gilead, GSK, Hoffmann
LaRoche, Janssen, Novartis, Pharmacyclics, Sunesis, Verastem
Research funding: AbbVie, AstraZeneca, Celgene, Gilead, GSK,
HoffmannLaRoche, Janssen, Novartis, Pharmacyclics, Sunesis,
Verastem
B. Eichhorst
Honoraria: HoffmannLaRoche, AbbVie, Celgene, Novartis, ArQule,
BeiGene, Gilead, AstraZeneca, Oxford Biomedica (UK), Adaptive
Biotechnologies
Research funding: HoffmannLaRoche, AbbVie, Janssen
Y. Jiang
Employment or leadership position: Genentec Inc.
M. Hallek
Honoraria: Roche, Gilead, Mundipharma, Janssen, Celgene, Pharma-
cyclics, AbbVie
Research funding: Roche, Gilead, Mundipharma, Janssen, Celgene,
Pharmacyclics, AbbVie
K. Fischer
Honoraria: AbbVie, HoffmannLaRoche
032 |CAPTIVATE PRIMARY ANALYSIS OF FIRSTLINE
TREATMENT WITH FIXEDDURATION IBRUTINIB PLUS
VENETOCLAX FOR CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)/
SMALL LYMPHOCYTIC LYMPHOMA (SLL)
C. S. L. Tam
1
, J. N. Allan
2
, T. Siddiqi
3
, T. J. Kipps
4
, R. Jacobs
5
, S. Opat
6
,
P. M. Barr
7
, A. Tedeschi
8
, L. Trentin
9
, R. Bannerji
10
, S. Jackson
11
,
B. Kuss
12
, C. Moreno
13
, E. SzaferGlusman
14
, K. Russell
15
, C. Zhou
16
,
J. Ninomoto
17
, J. P. Dean
18
, P. Ghia
19
, W. G. Wierda
20
1
Peter MacCallum Cancer Center & St. Vincent's Hospital and the
University of Melbourne, Haematology and Disease Group, Melbourne,
VIC, Australia,
2
Weill Cornell Medicine, Hematology/Oncology, New York,
USA,
3
City of Hope National Medical Center, Hematology, Duarte, USA,
4
UCSD Moores Cancer Center, Chronic Lymphocytic Leukemia, San Diego,
USA,
5
Levine Cancer Institute, Hematology and Medical Oncology,
Charlotte, USA,
6
Monash University, Clinical Haematology, Clayton, VIC,
Australia,
7
Wilmot Cancer Institute, University of Rochester Medical
Center, Hematology/Oncology, Rochester, USA,
8
ASST Grande Ospedale
Metropolitano Niguarda, Haematology, Milan, Italy,
9
Hematology and
Clinical Immunology Unit, Department of Medicine, University of Padova,
Hematology, Padova, Italy,
10
Rutgers Cancer Institute of New Jersey,
Hematology/Oncology, New Brunswick, USA,
11
Middlemore Hospital,
Haematology, Auckland, New Zealand,
12
Flinders University and Medical
66
-
SUPPLEMENT ABSTRACTS
Centre, Haemotology and Molecular Genetics, Bedford Park, SA, Australia,
13
Hospital de la Santa Creu i Sant Pau, Autonomous University of
Barcelona, Hematology, Barcelona, Spain,
14
Pharmacyclics LLC, an
AbbVie Company, Translational Medicine, Sunnyvale, USA,
15
Pharmacyclics LLC, an AbbVie Company, Clinical Program
Development, Sunnyvale, USA,
16
Pharmacyclics LLC, an AbbVie Company,
Biostatistics, Sunnyvale, USA,
17
Pharmacyclics LLC, an AbbVie Company,
Oncology, Sunnyvale, USA,
18
Pharmacyclics LLC, an AbbVie Company,
Oncology, Sunnyvale, USA,
19
Division of Experimental Oncology,
Università VitaSalute San Raffaele and IRCCS Ospedale San Raffaele,
Experimental Oncology, Milan, Italy,
20
University of Texas MD Anderson
Cancer Center, Leukemia, Houston, USA
Introduction: Over twothirds of patients (pts) in the Minimal Re-
sidual Disease (MRD) cohort of CAPTIVATE (PCYC1142;
NCT02910583), a multicenter phase 2 study, achieved undetectable
MRD (uMRD) with 12 cycles of ibrutinib (I) +venetoclax (V). 95% of
pts were progression free at 30 mo irrespective of subsequent ran-
domized treatment (Wierda, ASH 2020). Here we present results
from the Fixed Duration (FD) cohort.
Methods: Eligible pts were aged 70 y and had not received
previous treatment for CLL/SLL. Pts received 3 cycles of I then 12
cycles of I+V (I 420 mg/d orally; V rampup to 400 mg/d orally).
The primary endpoint was complete response (CR) rate, including
CR with incomplete recovery (CRi). Secondary endpoints were
overall response rate (ORR), duration of response, uMRD rate
(<10
–4
by 8color flow cytometry), progressionfree survival (PFS),
overall survival (OS), tumor lysis syndrome (TLS) risk reduction,
and safety.
Results: 159 pts were enrolled. Median age was 60 y. Highrisk
genomic features included del(17p)/TP53 mutation (17%), del(11q)
(18%), complex karyotype (19%), and unmutated IGHV (56%). 92% of
pts (n =147) completed planned I treatment; 94% (n =149)
completed planned V treatment. Median time on study was 27.9 mo
(range 0.8–33.2). Overall, CR rate was 55% (95% CI 48–63); CR rate
was consistent across highrisk subgroups. Of 88 pts who achieved a
CR; 89% of these pts (n =78) had durable CR (duration 1 y); 1 pt
died 7 mo after achieving a CR; 9 pts were not evaluable due to
followup of <1 y. ORR was 96%. Best uMRD response was achieved
in 77% of pts in peripheral blood (PB) and 60% in bone marrow (BM).
At 24 mo, PFS rate was 95% and OS rate was 98%. Similar results
were observed in pts without del(17p) (n =136) (Table). In the 27 pts
with del(17p)/TP53 mutation, CR rate was 56%; uMRD rate was 81%
in PB and 41% in BM; PFS at 24 mo was 84% (95% CI 63–94). After I
leadin, 94% of pts (32/24) with high baseline TLS risk based on tu-
mor burden shifted to medium/low risk. No TLS occurred. Most
adverse events (AEs) were grade 1/2. Neutropenia (33%), hyperten-
sion (6%), and decreased neutrophil count (5%) were the most
common grade 3/4 AEs. 4% of pts discontinued I and 2% dis-
continued V due to an AE.
Conclusions: Firstline I+V is an alloral, oncedaily, chemotherapy
free, fixedduration regimen that provides deep, durable responses
in pts with CLL/SLL, including those with highrisk genomic features.
CR, uMRD rates, PFS, and OS appear favorable. No new safety sig-
nals were identified; the safety profile of I+V was consistent with
known AEs for each agent.
EA previously submitted to ASCO and EHA 2021.
The research was funded by: Pharmacyclics LLC, an AbbVie Company
Keywords: Combination Therapies, Chronic Lymphocytic Leukemia
(CLL)
Conflicts of interests pertinent to the abstract
C. S. L. Tam
Consultant or advisory role: Janssen, Loxo, Roche, BeiGene, AbbVie
Honoraria: Janssen, AbbVie, BeiGene, Novartis, Pharmacyclics
Research funding: Janssen, AbbVie
J. N. Allan
Consultant or advisory role: AstraZeneca, Pharmacyclics, Janssen,
BeiGene, AbbVie, Genentech, Epizyme
Honoraria: AstraZeneca, Pharmacyclics, Janssen, BeiGene, AbbVie
Research funding: Celgene, Genentech, Janssen, TG Therapeutics
T. Siddiqi
Consultant or advisory role: Juno Therapeutics, Celgene, Kite
Pharma, AstraZeneca, BeiGene
Research funding: Kite, Juno, Celgene, AstraZeneca, TG Therapeu-
tics, Oncternal, Pharmacyclics, an AbbVie Company, BeiGene
Other remuneration: Speakers bureau: AstraZeneca, Pharmacyclics,
an AbbVie Company, Janssen
SUPPLEMENT ABSTRACTS
-
67
T. J. Kipps
Employment or leadership position: Moores Cancer Center
Consultant or advisory role: AbbVie, GenentechRoche, Gilead,
Pharmacyclics, an AbbVie Company, Celgene, Janssen, DAVA
Oncology
Stock ownership: Oncternal Therapeutics
Honoraria: Pharmacyclics, an AbbVie Company, AbbVie, Janssen,
Celgene, Genetech, Roche, Gilead Sciences, DavaOncology
Research funding: Pharmacyclics LLC, an AbbVie Company, MD
Anderson Cancer Center, Oncternal Therapeutics Inc, Crim, Velos,
Celgene
Educational grants: AbbVie, Pharmacyclics, an AbbVie Company,
Genentech, Roche, Janssen, Gilead, Celgene, Indy Hematology Re-
view, DAVA Oncology, GTherapeutics, Verastem, Bionest Partners,
OncLive
Other remuneration: Speakers bureau: Verastem, Pharmacyclics, an
AbbVie Company, Janssen, AbbVie, Genentech, Gilead, DAVA Phar-
maceuticals. Patents/Royalties/Intellectual Property: Cirmtuzumab
was developed by Thomas J. Kipps
R. Jacobs
Consultant or advisory role: AbbVie, Pharmacyclics, an AbbVie
Company, AstraZeneca, Verastem
Research funding: TG Therapeutics, Pharmacyclics, an AbbVie
Company
Other remuneration: Speakers bureau: AbbVie, Pharmacyclics, an
AbbVie Company AstraZeneca, Janssen, Sanofi, Genentech
S. Opat
Consultant or advisory role: Janssen, Roche, Gilead, AbbVie,
Mundipharma
Honoraria: Janssen, Roche, Gilead, AbbVie, Mundipharma
Research funding: Roche, Gilead, BeiGene, Pharmacyclics, an AbbVie
Company, AbbVie, Amgen, Janssen
P. M. Barr
Consultant or advisory role: Celgene, Pharmacyclics, an AbbVie
Company, AbbVie, Gilead, Seattle Genetics, Merck, Genentech,
Janssen, MorphoSys, AstraZeneca, TG Therapeutics
A. Tedeschi
Honoraria: Janssen, BeiGene, AstraZeneca, AbbVie
Other remuneration: Speakers bureau: Janssen, BeiGene, AstraZe-
neca, AbbVie
L. Trentin
Consultant or advisory role: AbbVie
Honoraria: Janssen, AbbVie
Research funding: Janssen
Educational grants: Roche, AbbVie, Janssen
R. Bannerji
Employment or leadership position: SanofiPasteur
Research funding: Pharmacyclics, an AbbVie Company, AbbVie,
Merck & Co., Inc., Regeneron, Genentech/Roche, Triphase
S. Jackson
Consultant or advisory role: AbbVie
Educational grants: Roche
Other remuneration: Speakers bureau: AbbVie
B. Kuss
Consultant or advisory role: AbbVie, Janssen, Merck, Takeda, Kyowa
Kirin, Mundipharma, Roche Pharmaceuticals
Stock ownership: Commonwealth Serum Laboratories
Honoraria: AbbVie, Janssen, Merck, Takeda, Kyowa Kirin, Mundi-
pharma, Roche Pharmaceuticals
Other remuneration: Speakers bureau: AbbVie, Janssen, Roche
Pharmaceuticals. Expert testimony: AbbVie
C. Moreno
Consultant or advisory role: Janssen, AbbVie, AstraZeneca, BeiGene
Research funding: AbbVie, Janssen
Other remuneration: Speakers bureau: Janssen
E. SzaferGlusman
Employment or leadership position: AbbVie
Stock ownership: AbbVie
K. Russell
Employment or leadership position: AbbVie
Stock ownership: AbbVie
C. Zhou
Employment or leadership position: AbbVie
Stock ownership: AbbVie
J. Ninomoto
Employment or leadership position: AbbVie
Stock ownership: AbbVie, Amgen, Celgene
J. P. Dean
Employment or leadership position: Pharmacyclics LLC, an AbbVie
Company
Stock ownership: Pharmacyclics LLC, an AbbVie Company
P. Ghia
Consultant or advisory role: AbbVie, Acerta/AstraZeneca, Adaptive,
ArQule, BeiGene, Celgene/Juno, Gilead, Janssen, Lilly/Loxo, Sunesis
Honoraria: AbbVie, Acerta/AstraZeneca, Adaptive, ArQule, BeiGene,
Celgene/Juno, Gilead, Janssen, Lilly/Loxo, Sunesis
Research funding: AbbVie, Gilead, Janssen, Novartis, Sunesis
W. G. Wierda
Other remuneration: Contracted research: GSK/Novartis, Abb-
Vie, Genentech, Pharmacyclics LLC, an AbbVie Company, Acerta,
Gilead Sciences, Juno Therapeutics, KITE Pharma, Sunesis, Mira-
gen, Oncternal Therapeutics, Cyclacel, Loxo Oncology, Janssen,
Xencor
68
-
SUPPLEMENT ABSTRACTS
033 |FIRST RESULTS OF A HEADTOHEAD TRIAL OF
ACALABRUTINIB VERSUS IBRUTINIB IN PREVIOUSLY TREATED
CHRONIC LYMPHOCYTIC LEUKEMIA
P. Hillmen
1
, J. C. Byrd
2
, P. Ghia
3
, A. P. Kater
4
, A. ChananKhan
5
, R. R.
Furman
6
, S. O'Brien
7
, M. N. Yenerel
8
, A. Illes
9
, N. Kay
10
, J. A. Garcia
Marco
11
, A. Mato
12
, J. PinillaIbarz
13
, J. F Seymour
14
, S. Lepretre
15
,
S. Stilgenbauer
16
, T. Robak
17
, P. Patel
18
, K. Higgins
19
, S. Sohoni
20
,
W. Jurczak
21
1
St. James's University Hospital, Experimental Haematology, Leeds, UK,
2
The Ohio State University Comprehensive Cancer Center, Hematology,
Columbus, USA,
3
Università VitaSalute San Raffaele and IRCCS Ospedale
San Raffaele, Experimental Oncology, Milano, Italy,
4
Amsterdam Univer-
sity Medical Center, Amsterdam, on behalf of Hovon, Hematology, Lym-
phoma and Myeloma Research, Amsterdam, Netherlands,
5
Mayo Clinic
Jacksonville, Hematology, Oncology, Jacksonville, USA,
6
Weill Cornell
Medicine, New York Presbyterian Hospital, Hematology, Oncology, New
York, USA,
7
Chao Family Comprehensive Cancer Center, University of
CaliforniaIrvine, Hematology, Oncology, Irvine, USA,
8
Istanbul University,
Istanbul Faculty of Medicine, Hematology, Istanbul, Turkey,
9
University of
Debrecen, Historical Auxiliary Sciences, Debrecen, Hungary,
10
Mayo Clinic
Rochester, Hematology, Rochester, USA,
11
Hospital Universitario Puerta
de HierroMajadahonda, "Unidad de Citogenetica Molecular Servicio de
Hematologia ", Madrid, Spain,
12
University of Pennsylvania, Chronic
Lymphocytic Leukemia, Philadelphia, USA,
13
Moffitt Cancer Center, Ma-
lignant Hematology, Tampa, USA,
14
Peter MacCallum Cancer Centre,
Royal Mselbourne Hospital, and University of Melbourne, Haematology,
Victoria, Australia,
15
Centre Henri Becquerel and Normandie University
UNIROUEN, Hématologie, Rouen, France,
16
University of Ulm, Internal
Medicine III, Haematology, Oncology, Rheumatology and Infectious Dis-
eases, Ulm, Germany,
17
Medican University of Lodz, Hematology, Lodz,
Poland,
18
AstraZeneca, Clinical Development Hematology, R&D Oncology,
South San Francisco, USA,
19
AstraZencea, Biostatistics, South San Fran-
cisco, USA,
20
AstraZeneca, Clinical Development Hematology, R&D
Oncology, South San Francisco, USA,
21
Maria SklodowskaCurie National
Research Institute of Oncology, Clinical Oncology, Krakow, Poland
Introduction: Increased selectivity of the Bruton tyrosine kinase in-
hibitor (BTKi) acalabrutinib (Aca) vs ibrutinib (Ib) may improve
tolerability. We conducted an openlabel, randomized, noninferiority,
phase 3 trial to compare Aca vs Ib in patients (pts) with chronic
lymphocytic leukemia (CLL).
Methods: Previously treated CLL pts with del(17p) or del(11q)
by central lab were randomized to receive oral Aca 100 mg
BID or Ib 420 mg QD (stratified by del(17p) status, ECOG PS [2
vs 1], and number of prior therapies [1–3 vs 4]) until pro-
gression or unacceptable toxicity. Primary endpoint was
progressionfree survival (PFS; IRCassessed); secondary endpoints
of allgrade atrial fibrillation (AF), grade 3 infection, Richter
transformation, and overall survival (OS) were assessed in hier-
archical order.
Results: 533 pts (Aca, n =268; Ib, n =265) were randomized
(median age 66 y; median 2 prior therapies; del(17p) 45.2%; del
(11q) 64.2%). At median followup of 40.9 mo (range 0.0–59.1),
Aca was noninferior to Ib with median PFS of 38.4 mo in both
arms (HR 1.00; 95% CI 0.79–1.27). Aca was statistically superior to
Ib in allgrade AF incidence (9.4% vs 16.0%; P=0.023). Among
other secondary endpoints, grade 3 infection (Aca: 30.8%, Ib:
30.0%) and Richter transformation (Aca: 3.8%, Ib: 4.9%) were
comparable between arms. Median OS was not reached in either
arm (HR 0.82 [95% CI 0.59–1.15]), with 63 (23.5%) deaths in the
Aca arm and 73 (27.5%) in the Ib arm. Among anygrade AEs in
20% of pts in either arm, Aca had lower incidence of hyperten-
sion (9.4%, 23.2%), arthralgia (15.8%, 22.8%), and diarrhea (34.6%,
46.0%) but higher incidence of headache (34.6%, 20.2%) and cough
(28.9%, 21.3%). AEs led to treatment discontinuation in 14.7% of
Acavs 21.3% of Ibtreated pts. Among anygrade events of clin-
ical interest, cardiac, hypertension, and bleeding events were less
frequent with Aca (Table).
Conclusions: In this first headtohead trial of BTKis in CLL, Aca
demonstrated noninferior PFS with less cardiotoxicity and fewer
discontinuations due to AEs vs Ib.
EA previously submitted to ASCO and EHA 2021.
TABLE 1Selected events of clinical interest
SUPPLEMENT ABSTRACTS
-
69
The research was funded by: Acerta Pharma, a member of the
AstraZeneca Group
Keywords: Chronic Lymphocytic Leukemia (CLL)
Conflicts of interests pertinent to the abstract
P. Hillmen
Consultant or advisory role: Janssen, Abbvie, AstraZeneca, Apellis
Honoraria: Janssen, Abbvie, Roche, AstraZeneca, Apellis
Research funding: Janssen, AbbVie, Roche, Pharmacyclics, Gilead
Educational grants: Janssen, Abbvie
J. C. Byrd
Employment or leadership position: Vincerx
Consultant or advisory role: Vincerx, Astrazeneca, Trillium, Novartis
Stock ownership: Vincerx
Honoraria: Syndax, Novartis, AstraZeneca, Trillium
Research funding: AstraZeneca
Other remuneration: several patents with small molecules unrelated
to this research
P. Ghia
Consultant or advisory role: AbbVie, AstraZeneca, ArQule/MSD,
BeiGene, Celgene/Juno/BMS, Gilead, Janssen, Lilly/loxo
Honoraria: AbbVie, AstraZeneca, ArQule/MSD, BeiGene, Celgene/
Juno/BMS, Gilead, Janssen, Lilly/loxo
Research funding: AbbVie, Gilead, Janssen, Novartis, Sunesis
A. P. Kater
Consultant or advisory role: Abbvie, Genentech, Janssen, Astra Zeneca
Honoraria: Abbvie, Genentech, Janssen, Astra Zeneca
Research funding: Abbvie, Genentech, Janssen, Astra Zeneca. BMS,
Celgene
Educational grants: Abbvie, Genentech, Janssen, Astra Zeneca
A. ChananKhan
Research funding: AstraZeneca
R. R. Furman
Consultant or advisory role: Pharmacyclics, Janssen Biotech, Gen-
entech/Roche, Loxo, TG Therapeutics, Verastem, Acerta Pharma,
AstraZeneca, Beigene, Incyte, OncoTracker, AbbVie, MorphoSys, Sanofi
Research funding: Acerta Pharma, TG Therapeutics; Honoraria:
Janssen, AstraZeneca
Educational grants: TG Therapeutics, Janssen Oncology
Other remuneration: Expert Testimony: AbbVie, Janssen Oncology;
Other: Incyte, Janssen Biotech
S. O'Brien
Consultant or advisory role: Gilead, Pharmacylics, TG Therapeutics,
Pfizer, Sunesis. Amgen, Astellas, Celgene, GSK, Janssen Oncology,
Aptose Biosciences Inc, Vaniam Group LLC, AbbVie, Alexion, Vera-
stem, Eisai, Juno Therapeutics, Vida Ventures, Autolus, Johnson and
Johnson, Merck, BMS
Research funding: Kite Regeneron, Acerta Pharma, Gilead, Pharma-
cylics, TG Therapeutics, Pfizer, Sunesis
M. N. Yenerel
Honoraria: Johnson and Johnson
Educational grants: Johnson and Johnson
A. Illes
Consultant or advisory role: Janssen, Celgene, Novartis, Pfizer,
Takeda, Roche
Research funding: Takeda, Seattle Genetics
Educational grants: Novartis, Janssen, Pfizer, Roche
N. Kay
Consultant or advisory role: MorphoSys, Celgene, Agios, CyomX
Therapeutics, AstraZeneca, Pharmacyclics, DAVA Pharmaceuticals,
June Therapeutics, Rigel, Oncotracker, BMS, AbbVie, Targeted
Oncology, Acerta Pharma, MEI Pharma, Sunesis Pharmaceuticals, TG
Therapeutics, Tolero Pharmaceuticals
Research funding: Pharmacyclics/Janssen, Tolero Pharmaceuticals,
Acerta Pharma, MEI Pharma, Celgene, Genentech, Sunesis Pharma-
ceuticals, AbbVie, TG Therapeutics, BMS
J. A. GarciaMarco
Consultant or advisory role: AbbVie, Janssen, Speakers Bureau:
AbbVie, Janseen, Roche
Research funding: Janssen
A. Mato
Consultant or advisory role: TG Therpeutics, AbbVie/Genentech,
Celgene, Adaptive Biotechnologies, Pharmacyclics, Verastem, John-
son and Johnson, Acerta Pharma, AstraZeneca, DTRM, Loxo/Lilly,
Curio, Merck, BMS/Pfizer
Research funding: Regeneron, TG Therpeutics, Sunesis Pharmaceu-
ticals, LOXO, AbbVie/Genentech, Pharmacyclics, Adaptive Bio-
technologies, Johnson and Johnson, Acerta Pharma, AstraZeneca,
DTRM, Genmab, Nurix
J. PinillaIbarz
Consultant or advisory role: Abbvie, Janssen, AstraZeneca, Novartis,
TG therapeutics, Takeda
Honoraria: Abbvie, Janssen, Takeda, AstraZeneca, Pharmacyclics,
Sanofi
Research funding: MEI, Sunesis
Other remuneration: Speaker's Bureau: Abbvie, Janssen, Astraze-
neca, Takeda
J. F. Seymour
Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Celgene,
Gilead, GSK, Hoffmann LaRoche, Janssen, Novartis
Honoraria: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK,
Hoffmann LaRoche, Janssen, Novartis
Research funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead,
GSK, Hoffmann LaRoche, Janssen, Novartis
Educational grants: AbbVie, Amgen, AstraZeneca, Celgene, Gilead,
GSK, Hoffmann LaRoche, Janssen, Novartis
Other remuneration: Speakers Bureau: AbbVie, Amgen, AstraZeneca,
Celgene, Gilead, GSK, Hoffmann LaRoche, Janssen, Novartis
70
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SUPPLEMENT ABSTRACTS
S. Stilgenbauer
Consultant or advisory role: AbbVie, Amgen, AstraZeneca, Celgene,
Gilead, GSK, Hoffmann LaRoche, Janssen, Novartis
Honoraria: AbbVie, Amgen, AstraZeneca, Celgene, Gilead, GSK,
Hoffmann LaRoche, Janssen, Novartis
Research funding: AbbVie, Amgen, AstraZeneca, Celgene, Gilead,
GSK, Hoffmann LaRoche, Janssen, Novartis
Educational grants: AbbVie, Amgen, AstraZeneca, Celgene, Gilead,
GSK, Hoffmann LaRoche, Janssen, Novartis
Other remuneration: Speakers Bureau: AbbVie, Amgen, AstraZeneca,
Celgene, Gilead, GSK, Hoffmann LaRoche, Janssen, Novartis
T. Robak
Consultant or advisory role: Sandoz, Takeda, Momenta
Research funding: Acerta Pharma, Roche, Janssen, AbbVie, Novartis,
BioGene, AstraZeneca, Pharmacyclics, UCB, Pfizer, Morphosys, UTX
TGR, GSK, Bristol Myers Squibb
Educational grants: Roche, Janssen, AbbVie; Honoraria: Sandoz, UCB,
Novartis, Octapharma, BioGene, AstraZeneca, Pharmacyclics
P. Patel
Employment or leadership position: AstraZeneca
Stock ownership: AstraZeneca
K. Higgins
Employment or leadership position: AstraZeneca, PROMETRIKA, LLC
S. Sohoni
Employment or leadership position: AstraZeneca
Stock ownership: Theravance
W. Jurczak
Consultant or advisory role: Mei pharma, Debiopharm, Loxo, Takeda,
Astra Zeneca, Beigene
Research funding: GSK, Acerta, Astra Zeneca, Beigene, Nordic
Nanovector, Incyte, Debiopharm, Incyte, Genenthech, Janssen, Loxo,
Mei Pharma, Morphosys, Takeda, TG Therapeutics
034 |BENDAMUSTINE, FOLLOWED BY OBINUTUZUMAB,
ACALABRUTINIB AND VENETOCLAX IN PATIENTS (PTS) WITH
RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKEMIA
(CLL): CLL2BAAG TRIAL OF THE GCLLSG
P. Cramer
1
, M. Fürstenau
1
, S. Robrecht
1
, A. Giza
1
, A. M. Fink
1
,
K. Fischer
1
, P. Langerbeins
1
, O. Al Sawaf
1
, E. Tausch
2
, C. Schneider
2
,
J. Schetelig
3
, P. Dreger
4
, S. Böttcher
5
, K. A. Kreuzer
1
, A. Schilhabel
6
,
M. Brüggemann
6
, M. Kneba
6
, C. M. Wendtner
7
, S. Stilgenbauer
2
,
B. Eichhorst
1
, M. Hallek
1
1
University of Cologne, Faculty of Medicine and University Hospital of
Cologne, Department I of Internal Medicine and German CLL Study
Group; Center for Integrated Oncology Aachen Bonn Cologne
Duesseldorf (CIO ABCD), Cologne, Germany,
2
University Hospital Ulm,
Department III of Internal Medicine, Ulm, Germany,
3
University
Hospital Carl Gustav Carus, Department I of Internal Medicine,
Dresden, Germany,
4
University Hospital Heidelberg, Department V of
Internal Medicine, Heidelberg, Germany,
5
University Hospital Rostock,
Department III of Internal Medicine, Rostock, Germany,
6
University of
SchleswigHolstein, Campus Kiel, Department II of Internal Medicine,
Kiel, Germany,
7
Klinikum Schwabing, Department of Hematology,
Oncology, Immunology, Palliative Care, Infectious Diseases and Tropical
Medicine, Munich, Germany
Introduction: The CLL2BAG trial had shown very favourable
response and minimal residual disease (MRD) rates with a sequential
treatment consisting of an optional bendamustine (B) debulking,
followed by a doublet combination of obinutuzumab (G) and ven-
etoclax (V) [Cramer et al, Lancet Oncol. 2018]. Following these re-
sults, the triplet combination adding the BTK inhibitor (BTKI)
acalabrutinib (A) was tested in the CLL2BAAG trial to further
improve efficacy.
Methods: An optional debulking with 2 cycles of B was recommended
in pts with lymphocyte counts 25.000/µl and/or lymph nodes 5cm
(70mg/m
2
d1&2 q28 days). In the induction, G (1000mg) was
administered 3 times in cycle 1 (days 1/2, 8 & 15) and every 4 weeks
in cycles 26. A (100mg bid) was added in cycle 2 followed by V in
cycle 3 with a dose rampup (to 400mg daily) over 5 weeks. In the
maintenance therapy, A and V remained unchanged while intervals of
G were increased to 3 months.
The primary endpoint was the rate of undetectable MRD (uMRD) in
PB at the end of induction therapy (defined as <104 by flow
cytometry, assessed centrally). Sample size was estimated with the
objective to test against the null hypothesis of 70% using a one
sided onesample binomial test on the basis of an assumed
improvement of uMRD rate to 90%. Secondary endpoints included
iwCLL responses, safety and survival parameters.
Results: Between January 2019 and June 2020, 46 pts were enrolled,
1 pt with a violation of inclusion/exclusion criteria and 2 induction
cycles was excluded from the analysis. The 45 evaluable pts had
relapsed/refractory (r/r) CLL with a median of one prior therapy
(range 14), 21 pts (47%) had already received a targeted agent,
including 8 pts with a BTKI, 7 pts with Vbased therapies, 3 pts with
both and 3 pts with idelalisib. Fourteen pts (32%) had a del(17p)/
TP53 mutation, 34 (76%) had an unmutated IGHV status and 12
(30%) a complex karyotype.
18 pts (40%) received B debulking, 27 (60%) pts immediately started
with the induction with G, A and V. 44 pts (98%) received 6 induction
cycles and 32 pts (71%) have thus far started with the maintenance
treatment.
At the end of the induction all pts responded, 8 pts (18%) had a CR/
CRi and 37 pts (82%) a PR. With an uMRD rate in PB of 76% (34 pts),
the primary endpoint was not met (95% CI 61%87%, p =0.258).
As of February 25th 2021, 430 adverse events (AEs) were reported,
including 29 SAEs (7%) and 69 AEs (16%) of CTC°34. Most common
were gastrointestinal AEs, cytopenias and infections.
Conclusion: Sequential treatment with B debulking, followed by the
triplet combination of G, A and V was well tolerated. Although the
SUPPLEMENT ABSTRACTS
-
71
primary endpoint was not met with given sample size, the ORR of
100% and a rate of uMRD of 76% in PB at the end of induction phase
compare favourably to other regimens for r/r CLL. The lower uMRD
rate may be explained by the redistribution phenomenon caused by
BTKI and could improve with continued maintenance treatment in
the long run.
The research was funded by: The research (IIT study) was funded by
AstraZeneca and F. HoffmannLaRoche.
Keywords: Chronic Lymphocytic Leukemia (CLL), Molecular Targeted
Therapies, Combination Therapies
Conflicts of interests pertinent to the abstract
P. Cramer
Consultant or advisory role: AbbVie and AstraZeneca
Honoraria: AbbVie, AstraZeneca, F. HoffmannLaRoche and Janssen
Cilag
Research funding: Acerta, AstraZeneca, Beigene, F. Hoffmann
LaRoche, Gilead, JanssenCilag and Novartis
Educational grants: AbbVie, AstraZeneca, F. Hoffmann LaRoche, and
JanssenCilag
A. M. Fink
Honoraria: Janssen
Research funding: Celgene
Educational grants: Abbvie
K. Fischer
Honoraria: AbbVie and F. HoffmannLaRoche
Educational grants: F. HoffmannLaRoche
P. Langerbeins
Honoraria: AbbVie, F. HoffmannLaRoche and JanssenCilag
Research funding: JanssenCilag
Educational grants: AbbVie, F. HoffmannLaRoche and JanssenCilag
O. Al Sawaf
Consultant or advisory role: AbbVie, AstraZeneca, Janssen, Gilead
and Roche
Honoraria: AbbVie, AstraZeneca, Janssen, Gilead and Roche
Research funding: AbbVie, BeiGene, Janssen and Roche
Educational grants: AbbVie, AstraZeneca, Janssen, Gilead and
Roche
E. Tausch
Consultant or advisory role: AbbVie, JanssenCilag, Roche
Honoraria: AbbVie, JanssenCilag, Roche
Research funding: AbbVie, JanssenCilag, Roche
J. Schetelig
Consultant or advisory role: AbbVie, AstzaZeneca, Janssen, Roche,
and Gilead
Honoraria: AbbVie, AstzaZeneca, Janssen, Roche, and Gilead
P. Dreger
Consultant or advisory role: AbbVie, AstraZeneca, bluebird bio,
Gilead, Janssen, Novartis, Riemser, Roche
Honoraria: AbbVie, AstraZeneca, Gilead, Novartis, Riemser, Roche
Research funding: Riemser
S. Böttcher
Honoraria: Roche, AbbVie, Becton Dickinson, Janssen, AstraZeneca,
Sanofi.
Research funding: JanssenCilag
K. A. Kreuzer
Consultant or advisory role: AbbVie, Amgen, F. HoffmannLaRoche,
Gilead, JanssenCilag and Mundipharma
Honoraria: AbbVie, Amgen, F. HoffmannLaRoche, Gilead, Janssen
Cilag and Mundipharma
Research funding: AbbVie, Amgen, F. HoffmannLaRoche, Gilead,
JanssenCilag and Mundipharma
M. Brüggemann
Consultant or advisory role: Affimed, Amgen, Incyte, Janssen,
Regeneron
Honoraria: Affimed, Amgen, Incyte, Janssen, Regeneron
Research funding: Affimed, Amgen, Incyte, Janssen, Regeneron
Educational grants: Affimed, Amgen, Incyte, Janssen, Regeneron
Other remuneration: none
C. M. Wendtner
Consultant or advisory role: AbbVie, HoffmannLaRoche, Genentech,
Gilead, GlaxoSmithKline, JanssenCilag, Mundipharma and
Pharmacyclics
Honoraria: AbbVie, HoffmannLaRoche, Genentech, Gilead, Glax-
oSmithKline, JanssenCilag, Mundipharma and Pharmacyclics
Research funding: AbbVie, HoffmannLaRoche, Genentech,
Gilead, GlaxoSmithKline, JanssenCilag, Mundipharma and
Pharmacyclics
Educational grants: AbbVie, HoffmannLaRoche, Genentech,
Gilead, GlaxoSmithKline, JanssenCilag, Mundipharma and
Pharmacyclics
S. Stilgenbauer
Consultant or advisory role: AbbVie, Amgen, BoehringerIngelheim,
Celgene, F. HoffmannLaRoche, Genentech, Genzyme, Gilead, Glax-
oSmithKline, JanssenCilag, Mundipharma, Novartis and
Pharmacyclics
Honoraria: AbbVie, Amgen, BoehringerIngelheim, Celgene,
F. HoffmannLaRoche, Genentech, Genzyme, Gilead, GlaxoSmithK-
line, JanssenCilag, Mundipharma, Novartis and Pharmacyclics
Research funding: AbbVie, Amgen, BoehringerIngelheim, Celgene, F.
HoffmannLaRoche, Genentech, Genzyme, Gilead, GlaxoSmithKline,
JanssenCilag, Mundipharma, Novartis and Pharmacyclics
Educational grants: AbbVie, Amgen, BoehringerIngelheim, Celgene, F.
HoffmannLaRoche, Genentech, Genzyme, Gilead, GlaxoSmithKline,
JanssenCilag, Mundipharma, Novartis and Pharmacyclics
B. Eichhorst
Consultant or advisory role: AbbVie, AstraZeneca, Celgene, F.
HoffmannLaRoche, Gilead, JanssenCilag
72
-
SUPPLEMENT ABSTRACTS
Research funding: AbbVie, AstraZeneca, Celgene, F. Hoffmann
LaRoche, Gilead, JanssenCilag
Educational grants: AbbVie, AstraZeneca, Celgene, F. Hoffmann
LaRoche, Gilead, JanssenCilag
M. Hallek
Consultant or advisory role: AbbVie, Amgen, Celgene, F. Hoffmann
LaRoche, Gilead, JanssenCilag and Mundipharma
Honoraria: AbbVie, Amgen, Celgene, F. HoffmannLaRoche, Gilead,
JanssenCilag and Mundipharma
Research funding: AbbVie, Amgen, Celgene, F. HoffmannLaRoche,
Gilead, JanssenCilag and Mundipharma
SESSION 5: PEDIATRIC LYMPHOMAS
035 |CURRENT STATUS AND CHALLENGES IN DIAGNOSIS OF
CHILDHOOD NHL
W. Klapper
1
1
Institute of Pathology, Hematopathology Section, University Hospital
SchleswigHolstein, Kiel, Germany
Over the last decades sequencing technology gave insight into
details of the moleculargenetic landscape and has changed defi-
nitions of Band Tcell lymphomas as well as inroduction of new
subtypes. Moreover, molecular testing has become a standard
proceedure in diagnostic pathology. Pediatric oncologist are facing
two major challenges. First, the vast majority of studies on new
diagnostic markers and subtypes of lymphomas have been con-
ducted in adult but patients only and second, most genetic data
derived from sequencing studies are neither of diagnostic nor of
predictive of prognostic use in pediatric patients. For clinicians and
pathologist it is a challenge is to sort out what information is
required to obtain optimal diagnostic certainty in a child suffering
from lymphoma. In this session, I will present a casebased lecture
to discuss if diagnostic standards can be defined for the most
frequent NonHodgkin lymphomas lymphomas in children and
adults with a specific focus on the differences to adults. I will
discuss that the major challenges in the diagnosis of lymphomas in
children and adolescents are probably not related to molecular
testing but to issues that appear trivial at a first glance such as
availability of sufficient biopsy material, clinical information, his-
topathological experience and a rational but limited testing strat-
egy unsing immunohistochemistry and molecular testing. In fact it
seems that despite tremendous progress in molecular insights
into lymphoma biology, for the most frequent entities of Non
Hodgkin lymphoma in young patients the requirements for diag-
nosis leading to optimal patient care are vastly unaltered over the
last decades.
Keywords: NonHodgkin (Pediatric, Adolescent, and Young
Adult)
Conflicts of interests pertinent to the abstract
W. Klapper
Consultant or advisory role: Takeda
Research funding: Takeda, Amgen, Regeneron
036 |DOSEADJUSTED EPOCHRITUXIMAB OR INTENSIFIED
BNHLBFMTYPE THERAPY FOR PEDIATRIC PRIMARY
MEDIASTINAL BCELL LYMPHOMA
F. Knörr
1
, M. Zimmermann
2
, A. Attarbaschi
3
, E. Kabíčková
4
, B.
MaeckerKolhoff
2
, S. Ruf
5
, I. Kühnle
6
, M. Ebinger
7
, A.K. Garthe
8
,
I. Oschlies
9
, W. Klapper
9
, B. Burkhardt
8
, W. Wößmann
1
1
UKE, Departement of Pediatric Hematology and Oncology, Hamburg,
Germany,
2
Hannover Medical School, Clinic for Pediatric Hematology and
Oncology, Hannover, Germany,
3
St. Anna Children's Hospital, Medical
University of Vienna, Department of Pediatric Hematology and Oncology,
Vienna, Austria,
4
University of Prague, Department for Paediatric
Haematology and Oncology, Prague, Czech Republic,
5
University of
Gießen, Pediatric Hematology and Oncology, Gießen, Germany,
6
University Medical Center Göttingen, Division of Pediatric Hematology
and Oncology, Göttingen, Germany,
7
University of Tübingen, Department
of Pediatric Hematology and Oncology, Tübingen, Germany,
8
University
Hospital of Münster, Pediatric Hematology and Oncology, Münster,
Germany,
9
Universitätsklinikum SchleswigHolstein, Campus Kiel, Insti-
tute of Pathology, Hematopathology Section and Lymph Node Registry,
Kiel, Germany
Introduction: There is no standard therapy for children and ado-
lescents with primary mediastinal large Bcell lymphoma (PMBCL).
Relapse rates reach up to 40% with chemotherapy regimen
designed for treatment of mature BNHL in children. Therefore,
treatment for children and adolescents was intensified in the B
NHL BFM 04 trial (B 04). Doseadjusted chemoimmunotherapy
with etoposide, prednisone, cyclophosphamide, doxorubicin and
rituximab (DAEPOCHR) has been reported as an alternative,
effective treatment strategy in adults and few children and was
subsequently introduced as treatment recommendation by the
NHLBFM study group.
Methods: Treatment for PMBCL in the B 04 trial (2004 2010) was
stratified by initial LDH values and intensified from the previous
NHLBFM 95 trial (N 95) by adding two treatment courses. The
infusion time of MTX in B 04 was 24 hours for all patients, while it
was 4 hours for 7/20 patients in N 95. From 2010 onward, patients
with PMBCL in the B 04 trial and the NHLBFM registry 2012
received DAEPOCHR. The recommendation was modified from the
original protocol by the limitation of the cumulative dose of doxo-
rubicin to 360 mg/m
2
and the application of at least one dose of
intrathecal chemotherapy.
We compared the efficacy of DAEPOCHR (n =67, 52 without 12
courses BFMtype pretreatment) and intensified BFMtype chemo-
therapy for mature BNHL (n =29) for children and adolescents with
PMBCL included in the B 04 trial and the NHLBFM registry 2012 to
the previous treatment strategy of the N 95 trial (n =20).
SUPPLEMENT ABSTRACTS
-
73
Results: Two patients were excluded because they received
different treatment. The median age of 116 patients was 16.2
years, 53% were female. For treatment with DAEPOCHR, B 04
and N 95, eventfree (EFS) survival at 5 years was 84% (95%
confidence interval (CI), 72 91%), 59% (CI, 39 74%), and 39%
(CI, 23 65%); survival (OS) was 90% (CI, 79 95%), 72% (CI, 51
88%) and 70% (CI, 45 85%), respectively. EFS and OS
with DAEPOCHR were significant superior to treatment with B
04 (p =.016 for EFS, p =.039 for OS) and N 95 (p <.001 for EFS
and p =.026 for OS). The difference in EFS observed be-
tween intensified BNHLBFM 04 and the previous treatment
regimen was not significant (p =.14). EFS for 52 patients receiving
DAEPOCHR without pretreatment was 87% (CI, 74 93%).
CNS was involved at relapse in four of 11 patients relapsing af-
ter DAEPOCHR in contrast to none of 22 after BFMtype B
NHLtherapy (p =.008). Except for younger age at diagnosis,
no risk factor for treatment failure with DAEPOCHR was
identified.
Conclusion: DAEPOCHR was superior to the previous
chemotherapy regimens for mature BNHL in children and ado-
lescents with PMBCL. The observed improvement in EFS with
intensified chemotherapy in the B 04 trial was not statistically
significant. A possibly higher risk for CNS relapse with DA
EPOCHR needs to be addressed in future collaborative clinical
trials.
EA previously submitted to regional or national meetings (up to
1000 attendees)
Keywords: NonHodgkin (Pediatric, Adolescent, and Young Adult),
Combination Therapies
No conflicts of interests pertinent to the abstract.
037 |AN OPENLABEL, PHASE 1/2 STUDY OF FRONTLINE
BRENTUXIMAB VEDOTIN +ADRIAMYCIN, VINBLASTINE, AND
DACARBAZINE IN PAEDIATRIC PATIENTS WITH ADVANCED
STAGE HODGKIN LYMPHOMA
A. R. K. Franklin
1
, F. A. V. Luisi
2
, M. A. Pianovski
3
, M. A. Salvino
4
,
F. Fagioli
5
, S. Epelman
6
, L. B De Abreu Lima
7
, R. E. Norris
8
, V. Odone
Filho
9
, M. Zecca
10
, C. Favre
11
, R. Kobayashi
12
, Y. Sidi
13
, F. Campana
14
,
E. J. Leonard
14
, F. Locatelli
15
1
Children's Hospital Colorado, Center for Cancer and Blood Disorders,
Aurora, Colorado, USA,
2
GRAACC/UNIFESP, Pediatria, São Paulo,
Brazil,
3
Erastinho Hospital (previously Erasto Gaertner Hospital),
Pediatric Oncology, Curitiba, Brazil,
4
IDOR, Salvador, Hospital Sao
Rafael, Hematology, Salvador, Brazil,
5
Regina Margherita Children's
Hospital, Department of Sciences of Public Health and Pediatrics, Turin,
Italy,
6
Hospital Santa Marcelina, Pediatric Oncology, São Paulo, Brazil,
7
INCA Instituto Nacional de Câncer, Hematology, Rio de Janeiro,
Brazil,
8
Cincinnati Childrens Hospital Medical Center, Cancer and Blood
Diseases Institute, Department of Pediatrics, Cincinnati, Ohio, USA,
9
ITACI Instituto De Tratamento Do Câncer Infantil, Faculdade De
Medicina Da Universidade De São Paulo, Departament De Pediatria,
São Paulo, Brazil,
10
Fondazione IRCCS Policlinico San Matteo, Pediatric
Hematology / Oncology, Pavia, Italy,
11
Azienda Ospedaliero
Universitaria Ospedale Pediatrico Meyer, Dipartimento di
Oncoematologia, Firenze, Italy,
12
Sapporo Hokuyu Hospital, Department
of Hematology/Oncology for Children and Adolescents, Sapporo, Japan,
13
Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly
owned subsidiary of Takeda Pharmaceutical Company Limited,
Statistics and Quantitative Sciences, Cambridge, Massachusetts, USA,
14
Millennium Pharmaceuticals Inc., Cambridge, MA, USA, a wholly
owned subsidiary of Takeda Pharmaceutical Company Limited,
KaplanMeier estimates of event free survival (EFS) by treatment for pediatric PMBCL
74
-
SUPPLEMENT ABSTRACTS
Department Clinical Sciences OTAU, Cambridge, Massachusetts, USA,
15
IRCCS Ospedale Pediatrico Bambino Gesù, Pediatric Hematology/
Oncology, Rome, Italy
Introduction: Paediatric Hodgkin lymphoma (HL) has high
cure rates, but in younger patients (pts) multiagent regimens are
associated with serious sequelae from radiation and alkylating
chemotherapy including: increased secondary malignancies,
cardiovascular disease, hypothyroidism, infertility, pulmonary
diseases, and infections. C25004 (NCT02979522) is a Phase (Ph)
1/2 openlabel study to assess the safety and efficacy of frontline
brentuximab vedotin +adriamycin, vinblastine, and dacarbazine
(A+AVD) in paediatric pts with advancedstage, classical
HL (cHL).
Methods: Eligible pts were aged 5 to <18 years, had untreated
stage III/IV cHL, Lansky/Karnofsky Performance Status (LKPS) 50,
and bidimensional measurable disease by radiography. In Ph1, pts
received up to 6 28day cycles of A+AVD on days 1 and 15 of
each cycle, with brentuximab vedotin given as a 36 mg/m
2
or 48
mg/m
2
dose. Toxicity was evaluated per National Cancer Institute
Common Terminology Criteria for Adverse Events, v4.03. Ph 1
primary objectives were to assess safety and tolerability and to
identify the recommended Ph2 dose (RP2D) of brentuximab
vedotin. Ph2 primary objectives were to assess the objective
response rate (ORR) (complete [CR] +partial remission [PR] rates),
and to determine the proportion of pts achieving PETnegativity
(Deauville score 1–3) after 2 cycles (PET2), and the proportion
of pts completing 6 cycles of therapy at the RP2D. The percentage
of pts receiving radiotherapy (RT) after study treatment and the
safety and tolerability of A+AVD were included as Ph2 secondary
endpoints.
Results: In total, 59 pts were enrolled (Ph1 n =8, Ph2 n =51),
median age was 14 years (range 6–17), 53% were male and me-
dian LKPS was 90.0 (range 70–100). RP2D was 48 mg/m
2
as re-
ported by Franklin et al. (ASH 2018, abstract 1644); all pts
received 6 cycles of A+AVD. Ph 1/2 results for the total popula-
tion (N =59) are reported hereafter. ORR per independent review
facility at end of treatment was 88% (95% CI: 77, 95), 76% of pts
(95% CI: 63, 86) achieved a CR. PET2rate was 90% (95% CI: 79,
96). After 17.31 months (median) followup 13 pts (22%) had
progressive disease. Safety data are summarised in the Table. The
most common anygrade treatmentemergent adverse events
(TEAEs) were vomiting (85%) nausea (75%), and neutropenia
(58%); 41% of pts experienced serious AEs (SAEs). There were no
onstudy deaths.
Conclusions: Frontline brentuximab vedotin (48 mg/m
2
)+AVD was
well tolerated providing high rates of ORR, CR, and PET2in paedi-
atric pts with advanced cHL, aligning with adult efficacy and safety
seen in ECHELON1. Patients continue in followup.
The research was funded by: Millennium Pharmaceuticals, Inc.,
Cambridge, MA, USA, a wholly owned subsidiary of Takeda Phar-
maceutical Company Limited.
Keywords: Hodgkin lymphoma, Molecular Targeted Therapies
Conflicts of interests pertinent to the abstract
F. A. V. Luisi
Employment or leadership position: GRAACC
Honoraria: GRAACC
M. A. Pianovski
Research funding: Millennium Pharmaceuticals, Inc., Cambridge, MA,
USA, a wholly owned subsidiary of Takeda Pharmaceutical Company
Limited
M. A. Salvino
Consultant or advisory role: Takeda Advisory Board
Research funding: Brentuximab Clinical Trials HSR PI
R. E. Norris
Employment or leadership position: Merck Pharmaceuticals
Educational grants: Merck Pharmaceuticals
SUPPLEMENT ABSTRACTS
-
75
M. Zecca
Consultant or advisory role: AMGEN, Bluebird, MEDAC
Educational grants: JAZZ Pharmaceuticals
Y. Sidi
Employment or leadership position: Millennium Pharmaceuticals Inc.,
Cambridge, MA, USA, a wholly owned subsidiary of Takeda Phar-
maceutical Company Limited
F. Campana
Employment or leadership position: Millennium Pharmaceuticals Inc.,
Cambridge, MA, USA, a wholly owned subsidiary of Takeda Phar-
maceutical Company Limited
E. J. Leonard
Employment or leadership position: Millennium Pharmaceuticals Inc.,
Cambridge, MA, USA, a wholly owned subsidiary of Takeda Phar-
maceutical Company Limited
Stock ownership: Millennium Pharmaceuticals Inc., Cambridge, MA,
USA, a wholly owned subsidiary of Takeda Pharmaceutical Company
Limited
038 |BRENTUXIMAB VEDOTIN WITH CHEMOTHERAPY IN
ADOLESCENTS AND YOUNG ADULTS (AYAS) WITH STAGE III OR
IV HODGKIN LYMPHOMA: A SUBGROUP ANALYSIS FROM THE
PHASE 3 ECHELON1 STUDY
H. E. Crosswell
1
, A. S. LaCasce
2
, N. L. Bartlett
3
, D. J. Straus
4
,
K. J. Savage
5
, P. L. Zinzani
6
, G. P. Collins
7
, M. A. Fanale
8
, K. Fenton
9
,
C. Dong
10
, H. H. Miao
11
, A. P. Grigg
12
1
Bon Secours Hematology Oncology, Bon Secours, St. Francis Health
System, Greenville, South Carolina, USA,
2
DanaFarber Cancer Institute,
Partners CancerCare, Boston, Massachusetts, USA,
3
Siteman Cancer
Center, Washington University School of Medicine, St. Louis, Missouri,
USA,
4
Lymphoma Service, Department of Medicine, Memorial Sloan Ket-
tering Cancer Center, New York, New York, USA,
5
BC, Cancer, Vancouver,
Canada,
6
Institute of Hematology “L. e A. Seràgnoli”, University of
Bologna, Bologna, Italy,
7
Oxford University Hospitals, NHS Trust, Oxford,
UK,
8
Medical Affairs, Seagen Inc., Bothell, Washington, USA,
9
Biostatistics,
Seagen Inc., Bothell, Washington, USA,
10
Takeda, Oncology, Cambridge,
Massachusetts, USA,
11
Takeda, Oncology, Cambridge, Massachusetts,
USA,
12
Department of Clinical Haematology, Austin Hospital, Austin, VIC,
Australia
Background: Classical hodgkin lymphoma (cHL) is a rare disease
that commonly occurs in adolescents and young adults (AYAs),
typically defined as 15 to 39 years. Given their young age at
presentation, key factors in treatment selection include not only a
high cure rate, but minimal longterm toxicities. Brentuximab
vedotin is a CD30directed ADC approved in combination with
doxorubicin, vinblastine, and dacarbazine chemotherapy (A+AVD)
for adults with previously untreated stage III/IV cHL based on
results from the phase 3 ECHELON1 trial. Recent 5year data
demonstrated a significantly improved PFS per investigator (INV)
vs doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD)
(HR, 0.69; 95% CI, 0.54–0.9; P =0.003) (Straus 2020). Here we
describe the key efficacy and safety results for AYA pts enrolled in
ECHELON1.
Methods: ECHELON1 (N =1334) is a global, openlabel, multi-
center, randomized trial of pts with previously untreated stage III/IV
cHL. A total of 771 AYAs (58%) received either A+AVD (n =396) or
ABVD (n =375) with a PET scan after cycle 2 (PET2). An analysis of
PFS (time from randomization to progression or death from any
cause) per INV was conducted.
Results: These results refer to the AYA subset. After a median
followup of 60.7 months (95% CI, 60.461.0), there was a 36%
reduction in the risk of progression or death with A+AVD vs ABVD
(HR 0.64; 95% CI, 0.450.92; P =0.013) with a 5year PFS of 86.3%
vs 79.4%, respectively, similar to the ITT population. The PFS benefit
of A+AVD vs ABVD was independent of PET2 status; PET2 positivity
(Deauville 45) was 6% and 8%, respectively.
On the A+AVD arm, 81 pts (20%) had at least one subsequent
anticancer therapy (including radiotherapy) vs 96 pts (26%) on the
ABVD arm; 26 pts (7%) on the A+AVD arm received subsequent high
dose chemotherapy and autologous stem cell transplant vs 32 pts
(9%) on the ABVD arm.
Anygrade peripheral neuropathy (PN) occurred in 64% and 40% of
pts on the A+AVD and ABVD arms, respectively. Resolution or
improvement of PN occurred in 8889% of pts on both arms. Ongoing
PN was predominantly Gr 1 (62%) and Gr 2 (26%), with 8 pts (3% of
the total cohort) on the A+AVD arm and 1 pt (<1%) on the ABVD
arm reporting ongoing Gr 3 PN. Seven pts (1.8%) and 5 pts (1.4%) on
the A+AVD and ABVD arms, respectively, reported a secondary
malignancy.
Subsequent pregnancies were reported in female pts (44 A+AVD; 26
ABVD) and partners of male pts (31 A+AVD; 30 ABVD). No stillbirths
were reported. All but 1 pt in each arm was <40.
Conclusions: Consistent with the ITT population, AYAs treated
with A+AVD compared to ABVD had a durable PFS benefit at this
significant 5year milestone. No impact on the rate of secondary
malignancies and a numerically greater number of pregnancies
were observed, outcomes of interest to AYAs. Additionally,
the majority of PN events improved or resolved over time. A+AVD
should be considered a treatment option for AYAs with stage
III/IV cHL.
EA previously submitted to ASCO and EHA 2021.
The research was funded by: Seagen Inc.
Keywords: Hodgkin lymphoma
Conflicts of interests pertinent to the abstract
H. E. Crosswell
Consultant or advisory role: Servier, Daiichi Sankyo
Stock ownership: Kiyatec, BMS, Seagen Inc., Gliead Sciences, Abbvie,
Pfizer
76
-
SUPPLEMENT ABSTRACTS
A. S. LaCasce
Consultant or advisory role: Forty Seven, BMS, Seagen Inc.,
Humanigen
Research funding: Sanofi, Celgene, Seagen Inc.,
Other remuneration: Speakers' Bureau Research to Practice
N. L. Bartlett
Consultant or advisory role: Seagen Inc., Roche/Genentech, ADC
Therapeutics, BTG, Acerta Pharma
Research funding: Seagen Inc., Kite Pharma, Merck, BMS, Celgene,
Immune Design, Forty Seven, Janssen, Pharmacyclics, Millennium,
ADC Therapeutics, Autolus, Roche/Genentech, Pfizer, Affirmed
Therapeutics
D. J. Straus
Consultant or advisory role: Takeda, Seagen Inc.
Research funding: Seagen Inc.
K. J. Savage
Consultant or advisory role: Seagen Inc., BMS, Merck, Servier, Abb-
vie, Gilead Sciences, AstraZeneca
Honoraria: Seagen Inc., BMS, Merck, Abbvie, Gilead Sciences,
AstraZeneca, Kyowa Kirin, Novartis, Novartis Canada Pharmaceuti-
cals Inc.
Research funding: Roche, BMS
Educational grants: Seagen Inc.
P. L. Zinzani
Consultant or advisory role: EUSA Pharma, Takeda, Merck, Roche,
Abbvie
Honoraria: EUSA Pharma, Takeda, Merck, Roche, Abbvie
Other remuneration: Speakers' Bureau EUSA Pharma, Takeda,
Merck, Gilead Sciences, Novartis
G. P. Collins
Consultant or advisory role: Roche, Takeda, Incyte, Pfizer, MSD, Celgene,
Beigene, Daiichi Sankyo, Celleron Therapeutics, ADC Therapeutics
Honoraria: Roche, Takeda, Gilead Sciences, Pfizer, Novartis, Daiichi
Sankyo, Incyte, Celleron Therapeutics, MSD Oncology, BeiGene, ADC
Therapeutics
Research funding: MSD Oncology, Celgene, Celleron Therapeutics,
BMS, Amgen
Other remuneration: Speakers' Bureau Roche, Takeda, Novartis,
Gilead Sciences
M. A. Fanale
Employment or leadership position: Seagen Inc.
Consultant or advisory role: Spectrum Pharmaceuticals, Amgen,
Merck, BMS, Seagen Inc.
Stock ownership: Seagen Inc.
Honoraria: Seagen Inc., Takeda, Research to Practice, Plexus, BMS
Research funding: Millennium, Seagen Inc., Novartis, MedImmune,
Celgene, Molecular Templates, Genentech, Gilead Sciences, BMS,
Merck, ADC Therapeutics, Pharmacyclics, Takeda
Educational grants: Takeda, Spectrum Pharmaceuticals, Research to
Practice, Plexus, BMS, Merck, Seagen Inc.
K. Fenton
Employment or leadership position: Seagen Inc.
Stock ownership: Seagen Inc.
Educational grants: Seagen Inc.
C. Dong
Employment or leadership position: Takeda
Stock ownership: Seagen Inc., Takeda
H. H. Miao
Employment or leadership position: Takeda
Stock ownership: Takeda
A. P. Grigg
Consultant or advisory role: MSD Oncology, Janssen, Novartis
Honoraria: Roche, MSD
039 |A UK POPULATIONBASED STUDY OF NONHODGKIN
LYMPHOMA IN TEENAGERS AND YOUNG ADULTS (TYA)
INCIDENCE, TREATMENT AND OUTCOMES
R. Carr
1
, A. Davies
2
, B. Uttenthal
3
, M. Lamb
4
, J. Fidalgo
1
,
B. Carpenter
5
1
Guy's & St Thomas' Hospital, Haematology, London, UK,
2
Southampton
NCRI/CR UK Experimental Cancer Medicines Centre, Haematology,
Southampton, UK,
3
Addenbrookes Hospital, Paediatric Oncology,
Cambridge, UK,
4
Department of Health Sciences University of York,
Haematological Malignancy Research Network, York, UK,
5
University
College Hospital, Haematology, London, UK
Introduction: NHL is a common malignancy in young people.
The disease spectrum differs from older adults, it is frequently
difficult to manage and few recruited into trials. To gain a whole
population view of disease incidence and outcomes, and provide
evidence for trial design and optimised treatment strategies, this
study examines diagnosis, treatment and outcome data from 2 co-
horts of patients.
Methods: The 2 study cohorts comprises patients aged 15 to 29y;
i) a 3 year ‘Population Cohort’ of all cases diagnosed in England
20152017 based on Cancer Registry records; ii) a 4 year
contemporaneous ‘Consented Study Cohort’ of patients recruited
at 29 hospitals, 21 being Regional Cancer Centres, diagnosed over
4y 20152018. Population data includes demographics, diagnosis,
place of care, vital status; Consented data includes diagnostic pa-
thology, staging, treatment and response, with relapses and deaths
to January 2021.
Results: Population Cohort 624 patients with 22 NHL subtypes.
Incidence increased with age, 1519y (n =123) 2024y (n =206) 25
29y (n =295), particularly Diffuse Large Bcell Lymphoma (DLBCL) (n
SUPPLEMENT ABSTRACTS
-
77
=43, 70, 124, by age respectively). All NHL subtypes were more
common in males except for Mediastinal Bcell (PMBL) more com-
mon in females. For all NHLs combined, survival was not influenced
by gender or age but differed by place of care. 2y OS of patients aged
1524y treated at the 29 Consented Study hospitals was 86% and
74% at other, mostly smaller district hospitals, Hazard Ratio 1.75
(0.94, 3.26).
Consented Study Cohort 392 patients were recruited, 1519y (n =
111), 2024y (n =148), 2529y (n =133). 27 NHL subtypes were
recorded. Presentation with advanced disease was common; of 104
DLBCLs, 15% had NCCI IPI score of 45 and 18% had 3 extranodal
disease sites.
Unexpected was frequent failure to respond to firstline therapy in
DLBCL and PMBL. 8/81 (10%) DLBCLs with complete treatment
records died with refractory disease and 9 (11%) required 2 lines
to achieve remission. 4/60 (7%) PMBLs died with refractory dis-
ease and 19 (32%) remained PET positive after firstline chemo-
therapy, needing further chemotherapy or radiotherapy to achieve
remission.
There was variation between hospitals in treatment regimens
used for individual diseases. The effect of treatment on survival
being most marked for Burkitt's Lymphoma aged 1524y. Of a
total 32 cases, 23 were treated with (R)CODOXM±IVAC, 7
died (OS 69%); 9 treated on the (R)FAB/LMB96 protocol, 1 died
(OS 89%). This observation needs investigation in a randomised
trial.
Conclusions: NHL in teenage and young adult patients is challenging
to manage. Advanced disease and resistance to first line treatment is
common. Our findings support treatment of these cases guided by
experienced cancer centres. The detailed information gained by this
national collaboration provides the evidence base for future trials
and treatment strategies.
The research was funded by: Leukaemia UK
Gilead UK and Ireland Fellowship Programme
Keywords: NonHodgkin (Pediatric, Adolescent, and Young
Adult)
No conflicts of interests pertinent to the abstract.
SESSION 6: LYMPHOMA BIOLOGY 1
040 |MOLECULAR SUBCLUSTERS OF FOLLICULAR
LYMPHOMA: A REPORT FROM THE UK's HAEMATOLOGICAL
MALIGNANCY RESEARCH NETWORK
S. Crouch
1
, D. Painter
1
, S. Barrans
2
, E. Roman
1
, P. Beer
3
, S. Lacy
1
,
S. Cooke
3
, N. Webster
2
, P. Glover
2
, S. van Hoppe
2
, P. J. Campbell
4
,
D. J. Hodson
5
, R. Patmore
6
, C. Burton
2
, A. G. Smith
1
, R. Tooze
2
1
University of York, Epidemiology and Cancer Statistics Group,
Department of Health Sciences, York, UK,
2
Leeds Teaching Hospitals
NHS Trust, Haematological Malignancy Diagnostic Service, Leeds, UK,
3
University of Glasgow, Glasgow Precision Oncology Laboratory,
Glasgow, UK,
4
Wellcome Trust Sanger Institute, Cancer, Ageing and
Somatic Mutation Programme, Cambridge, UK,
5
University of
Cambridge, Wellcome–MRC CambridgeStem Cell Institute, Cambridge,
UK,
6
Hull University Teaching Hospitals NHS Trust, Queen's Centre for
Oncology and Haematology, Hull, UK
Follicular lymphoma (FL), while underpinned by apparently
shared molecular pathogenesis, reflects a heterogeneous disease
entity. At a molecular level it remains unclear whether FL can be
resolved into recurrent mutational clusters or pathogenetic
pathways.
Here we report the results of targeted sequencing (293 genes) and
robust cluster analysis as previously applied in DLBCL to a
populationbased cohort of FL (n =548) from the Haematological
Malignancy Research Network (catchment population of 4 million,
14 centers). This cohort with full clinical followup includes 96 cases
who underwent transformation to DLBCL, with 26 paired samples
sequenced.
FL cases had a median of 6 (IQR 48) driver mutations per sample.
Most prevalent events were in KMT2D,CREBBP,BCL2,TNFRSF14,
EZH2,STAT6 &BCL7A. The most common mutation hot spots were
EZH2 codon 646, and STAT6 codon 419. Potential targets (22 genes)
of aberrant somatic hypermutation (aSHM) were amongst the most
frequently mutated. After signaltonoise filtering 31 genetic features
were suitable for cluster analysis. The stringent Bayesian Information
Criterion (BIC) or sensitive Akaike Information Criterion (AIC)
resolved 2 (BIC) or 3 (AIC) robust clusters. Both separated FL with
multiple aSHM target gene mutations (FL_aSHM) from the
remainder. AIC resolved FL_aSHM (10.6%), and FL characterized by
STAT6,CREBBP and TNFRSF14 mutations (21.0%, FL_STAT6) from
the remainder (FL_Com, 68.4%). No significant differences in sex or
FLIPI were evident between the clusters. Patients in FL_aSHM were,
on average, 4.8 years older than those in other clusters (p =0.007).
Stage distributions differed: FL_aSHM had excess of stage III,
FL_STAT6 of stages I & II, and FL_Com of stage IV. No overall survival
(OS) differences between clusters were detected in patients initially
managed by Watch and Wait, but OS AIC cluster differences were
detectable in those initially managed in other ways (p =0.04). Evi-
dence for an adverse OS outcome for FL_aSHM relative to FL_Com (p
=0.03), did not persist after adjustment for age. The strongest pre-
dictor for OS at individual gene level was aSHM target HIST1H2AC
(HR =3.10, 95% CI =1.64, 5.86). Transformation showed no evi-
dence of imbalance between FL molecular subtypes, while 2genes
(TP53 and CDKN2A) were linked in univariate modelling to adverse
hazard ratios. The predominant mutational pattern in 26paired
transformation subjects supported branching evolution.
This populationbased analysis provides evidence for distinct mech-
anistic entities in FL, with aSHM burden and STAT6 mutation status
providing key determinants of this heterogeneity. In contrast to
DLBCL, we did not find evidence that tumour genetics provides a
strong marker for predicting patient outcome in FL. Instead we
speculate that factors related to the microenvironment or host im-
mune system may have a greater influence on patient survival.
78
-
SUPPLEMENT ABSTRACTS
The research was funded by: Blood Cancer UK (grant num-
ber 15037), Cancer Research UK (grant number A29685) and the
National Institute for Health Research (grant number RPPG0613
20002) funded the majority of this study. Genetic sequencing
was funded by 14M Genomics, a startup company that ceased
trading February 2016. DJH was funded by a clinician scientist
fellowship from the MRC and receives core funding from Well-
come and MRC to the WellcomeMRC Cambridge Stem Cell
Institute.
Keywords: Genomics, Epigenomics, and Other Omics, Indolent
nonHodgkin lymphoma, Pathology and Classification of
Lymphomas
No conflicts of interests pertinent to the abstract.
041 |SOMATIC ALTERATIONS IN FOLLICULAR LYMPHOMA
ASSOCIATE WITH UNIQUE TUMORCELL TRANCRIPTIONAL
STATES AND TUMORIMMUNE MICROENVIRONMENTS
J. Krull
1
, K. Wenzl
1
, M. K. Manske
1
, M. A. Hopper
1
, M. C. Larson
2
,
V. Sarangi
2
, P. Barman
2
, M. R. Serres
1
, S. Khan
1
, A. J. Novak
1
,
M. J. Maurer
2
, Z. Yang
1
, L. Rimsza
3
, B. K. Link
4
, T. M. Habermann
1
,
S. M. Ansell
1
, R. L. King
5
, J. R. Cerhan
2
, J. P. Novak
2
1
Mayo Clinic, Hematology, Rochester, Minnesota, USA,
2
Mayo Clinic,
Health Science Research, Rochester, Minnesota, USA,
3
Mayo Clinic,
Laboratory Medicine and Pathology, Phoenix, Arizona, USA,
4
University of
Iowa, Hematology, Iowa City, Iowa, USA,
5
Mayo Clinic, Hematopathology,
Rochester, Minnesota, USA
Background: While significant advances have been made in our un-
derstanding of FL biology, genomic studies to date have primarily
focused on prognostic (M7FLIPI), pathological designation (Grade 1
3b), or understanding transformation to DLBCL. Conclusions from
these studies are based on either small cohorts or targeted
sequencing panels, with no largerscale, integrated WES and RNAseq
studies being performed. Together, this presents an opportunity for a
comprehensive characterization of FL. Using a novel cohort of 93 FL
tumors, we have explored the transcriptomic signature of purified FL
B cells, and identified unique molecular subsets which are defined by
distinct pathway activation, immune content, and genomic
signatures.
Methods: Frozen pretreatment tumor biopsies from 93 FL patients
enrolled in the University of Iowa/Mayo Clinic Lymphoma SPORE
were used. RNAseq on MACS sorted FL B cells and WES was per-
formed and processed in the Mayo Clinic Genome Analysis Core.
Novel driver genes were identified using 20/20+driver analysis.
Matching CyTOF data was aquired from a previously published
SUPPLEMENT ABSTRACTS
-
79
dataset. Downstream analyses were perfomed in R using established
packages.
Results: Unsupervised clustering of RNAseq data identified three
distinct patient groups, C1 (n =24) and C2 (n =25), and C3 (n =
43). NMFderived cluster metagenes revealed significant pathway
association with DNA repair and stress response (C1), typeI IFN
signaling (C2), and epigenetic modulation (C3), differentiating be-
tween the 3 groups. VIPER master regulator activity inferencing
revealed that these pathways were likely being controlled by dif-
ferential activity in NFkB, IRFs, STAT1, BCL6, and FOXO1. The
metagenes significantly enriched for remnants of specific germinal
center programs, such as lightzone (C1), prememory (C2), and a
prelightzone intermediate (C3). To assess the contribution of the
tumor microenvironment (TME), available paired CyTOF data
revealed a wide variety of immune content in C1 that consisted
mostly of Tfh and myeloid cells, an active TME in C2, with sig-
nificant quantities of CD8 T cell and NK cell populations, and a
poorly populated immune compartment in C3, compared to C1 and
C2. Finally, somatic driver mutations and copy number alterations
from WES were identified, and associated with the three clusters.
The three groups distinguished themselves by significant enrich-
ment of alterations in TNFAIP3 (C1), host defense genes SNRNP200
and IRF8 (C2) and chromatin modifiers such as KMT2D and
CREBBP (C3).
Conclusion: Using a multiomic approach, three unique FL tumor B
cell states were identified which are linked to specific genetic
events and TME composition. This study improves the under-
standing of the mechanisms driving FL tumors and motivates
further investigation into transcriptional consequences of genetic
events, as well as potential tumor intrinsic factors that may in-
fluence the TME.
The research was funded by: NIHP50 CA097274 to J.R.C. and
A.J.N.
Keywords: Genomics, Epigenomics, and Other Omics, Tumor Biology
and Heterogeneity, Indolent nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
J. Krull
Research funding: Bristol Myers Squibb
J. P. Novak
Research funding: Bristol Meyers Squibb
042 |CREBBP MEDIATED ACETYLATION OF KMT2D IN
NORMAL AND TRANSFORMED GC B CELLS
S. Vlasevska
1
, L. GarciaIbanez
1
, R. Duval
1
, A. B. Holmes
1
, R. Jahan
1
,
K. Basso
2
, R. DallaFavera
2
, L. Pasqualucci
2
1
Columbia University, Institute for Cancer Genetics, New York, New
York, USA,
2
Columbia University, Institute for Cancer Genetics, the
Department of Pathology and Cell Biology, and the Herbert
Irving Comprehensive Cancer Center, New York, New York,
USA
Introduction: Perturbation of epigenetic reprogramming is a hall-
mark of germinal center (GC) derived follicular lymphoma (FL) and
diffuse large B cell lymphoma (DLBCL), which harbor highly recurrent
somatic mutations of histone/chromatin modifier genes. Among these
genes, those encoding the KMT2D methyltransferase and the
CREBBP acetyltransferase are the most commonly mutated,
respectively accounting for 6080% of FL and >40% of DLBCL
belonging to the EZB/C3 genetic subgroup. We have shown that
these enzymes represent early events in the history of FL/DLBCL,
and act as haploinsufficient tumor suppressors by accelerating the
development of BCL2translocation driven lymphomas in vivo. The
aim of this study was to investigate the functional interaction be-
tween KMT2D and CREBBP and their combined role in vivo in
lymphomagenesis.
Methods: We used biochemical and genetic approaches to investi-
gate whether KMT2D is a substrate of CREBBPmediated acetyla-
tion, contrast their chromatin binding pattern (ChIPSeq), and study
the functional relevance of this posttranslational modification in
normal GC B cells and DLBCL. Compound GCspecific Crebbp;Kmt2d
haploinsufficient mice, mimicking the frequent coexistence of these
lesions in FL and DLBCL, were then interrogated to assess the bio-
logical consequences of this interaction in GC responses and
lymphomagenesis.
Results: We found that KMT2D is acetylated in GC B cells as well
as in DLBCL cell lines carrying wildtype (WT) CREBBP/KMT2D
alleles. CREBBP catalyzes this modification in vitro and in vivo, and
this activity is lost in lymphomaassociated CREBBP proteins car-
rying truncating or missense mutations inactivating the HAT
domain. Lossof function assays in isogenic WT vs CREBBPor
EP300 deficient DLBCL cells showed that CREBBP is the prefer-
ential acetyltransferase. Of note, genetic disruption or pharmaco-
logic blockade of CREBBP led to a measurable reduction in
H3K4me1, the histone modification catalyzed by KMT2D, indi-
cating a role for KMT2D acetylation in modulating its enzymatic
activity. In vivo, GCspecific combined haploinsufficiency of
KMT2D and CREBBP induced GC hyperplasia which was signifi-
cantly more prominent as compared to individual deletion of these
two genes.
Conclusions: Our data reveal a physiologically relevant role for
CREBBP in acetylating the KMT2D protein, and suggest that
this posttranslational modification acts as a modulator of its activity.
These findings imply that CREBBP mutant tumors bear
KMT2D functional insufficiency, suggesting that CREBBP/KMT2D
haploinsufficiency facilitates the expansion of the common precursor
cell before acquisition of secondary genetic events leading to FL and/
or DLBCL. CREBBPtargeted epigenetic therapies may add to the
therapy in KMT2D mutated tumors.
80
-
SUPPLEMENT ABSTRACTS
Keywords: Genomics, Epigenomics, and Other Omics,
Aggressive Bcell nonHodgkin lymphoma, Indolent nonHodgkin
lymphoma
No conflicts of interests pertinent to the abstract.
043 |GENETIC AND PHENOTYPIC ATTRIBUTES OF SPLENIC
MARGINAL ZONE LYMPHOMA
F. Bonfiglio
1
, A. Bruscaggin
1
, F. Guidetti
1
, L. Terzi di Bergamo
1
,
M. Faderl
1
, V. Spina
1
, A. Condoluci
2
, L. Bonomini
3
, G. Forestieri
1
,
R. Koch
1
, D. Piffaretti
1
, K. Pini
1
, M. C. Pirosa
2
, M. G. Cittone
2
,
A. Arribas
4
, M. Lucioni
5
, G. Ghilardi
2
, W. Wu
1
, L. Arcaini
6
,
M. J. Baptista
7
, G. Bastidas
8
, S. Bea
9
, R. Boldorini
10
, A. Broccoli
11
,
V. Canzonieri
12
, L. Cascione
4
, L. Ceriani
13
, S. Cogliatti
14
,
E. Derenzini
15
, L. Devizzi
16
, S. Dietrich
17
, A. R. Elia
18
, F. Facchetti
19
,
G. Gaidano
20
, J. F. Garcia
21
, B. Gerber
2
, P. Ghia
22
, M. G. Da Silva
23
,
G. Gritti
24
, A. Guidetti
16
, F. Hitz
25
, G. Inghirami
26
, M. Ladetto
27
,
A. LopezGuillermo
28
, E. Lucchini
29
, A. Maiorana
30
, R. Marasca
31
,
E. Matutes
32
, V. Meignin
33
, M. Merli
34
, A. Moccia
35
, M. Mollejo
36
,
C. Montalban
37
, U. Novak
38
, D. G. Oscier
39
, F. Passamonti
40
,
F. Piazza
41
, S. Pizzolitto
42
, E. Sabattini
43
, G. Salles
44
, E. Santam-
brogio
45
, L. Scarfó
22
, A. Stathis
35
, G. Stüssi
2
, J. T. Geyer
46
, G. Tapia
47
,
C. Thieblemont
48
, T. Tousseyn
49
, A. Tucci
50
, C. Visco
51
, U. Vitolo
45
,
T. Zenz
52
, P. L. Zinzani
53
, H. Khiabanian
54
, A. Calcinotto
18
,
F. Bertoni
4
, G. Bhagat
55
, E. Campo
9
, L. De Leval
56
, S. Dirnhofer
57
,
S. A. Pileri
58
, M. Án. Piris
59
, A. TraverseGlehen
60
, A. Tzankov
57
,
M. Paulli
5
, M. Ponzoni
61
, L. Mazzucchelli
62
, F. Cavalli
63
, E. Zucca
35
,
D. Rossi
1
1
Institute of Oncology Research, Experimental Hematology, Bellinzona,
Switzerland,
2
Oncology Institute of Southern Switzerland, Division of
Hematology, Bellinzona, Switzerland,
3
International Extranodal
Lymphoma Study Group, IELSG, Bellinzona, Switzerland,
4
Institute of
Oncology Research, Lymphoma Genomics, Bellinzona, Switzerland,
5
Fondazione IRCCS Policlinico San Matteo, Unit of Anatomic
Pathology, Pavia, Italy,
6
Fondazione IRCCS Policlinico San Matteo,
Division of Hematology, Pavia, Italy,
7
Josep Carreras Leukaemia
Research Institute, Lymphoid neoplasms Group, Badalona, Spain,
8
Hospital Clínic i Provincial de Barcelona, Division of Hematology,
Barcelona, Spain,
9
Hospital Clínic, Pathology Department, Barcelona,
Spain,
10
University of Eastern Piedmont, Division of Pathology, Novara,
Italy,
11
IRCCS Azienda OspedalieroUniversitaria di Bologna, Istituto di
Ematologia, Bologna, Italy,
12
CRO Aviano National Cancer Institute,
Pathology Unit, Aviano, Italy,
13
Imaging Institute of Southern
Switzerland, Clinic of Nuclear Medicine and PETCT centre, Bellinzona,
Switzerland,
14
Kantonsspital St. Gallen, St.Gallen, Institute of Pathol-
ogy, St.Gallen, Switzerland,
15
IEO, European Institute of Oncology
IRCCS, Oncohematology Div., Milan, Italy,
16
Fondazione IRCCS Isti-
tuto Nazionale dei Tumori di Milano, Division of Hematology, Milan,
Italy,
17
University Hospital Heidelberg, Division of Hematology, Hei-
delberg, Germany,
18
Institute of Oncology Research, Cancer
Immunotherapy, Bellinzona, Switzerland,
19
University of Brescia School
of Medicine, Department of Molecular and Translational Medicine,
Brescia, Italy,
20
University of Eastern Piedmont, Division of hematol-
ogy, Novara, Italy,
21
MD Anderson Cancer Center, Division of Pa-
thology, Madrid, Spain,
22
IRCCS Ospedale San Raffaele and Università
VitaSalute San Raffaele, Division of Hematology, Milan, Italy,
23
Instituto Português de Oncologia de Lisboa, Division of Hematology,
Lisbon, Portugal,
24
Azienda Ospedaliera Papa Giovanni XXIII, Division
of Hematology, Bergamo, Italy,
25
Kantonsspital St. Gallen, Division of
Hematology, St. Gallen, Switzerland,
26
Weill Cornell Medical College,
Department of Pathology and Laboratory Medicine, New York, New
York, USA,
27
Azienda Ospedaliera SS Antonio e Biagio, Division of
Hematology, Alessandria, Italy,
28
Hospital Clínic i Provincial de Bar-
celona, Division of Lymphoid neoplasms, Barcelona, Spain,
29
Azienda
Sanitaria Universitaria Giuliano Isontina, Division of Hematology,
Trieste, Italy,
30
Universitá degli Studi di Modena e Reggio Emilia, Di-
vision of Pathology, Modena, Italy,
31
University of Modena and Reggio
Emilia, Department of Medical and Surgical Sciences, Modena, Italy,
32
Hospital Clínic i Provincial de Barcelona, Haematopathology Unit,
Barcelona, Spain,
33
Saint Louis Hospital, Division of Pathology, Paris,
France,
34
University of Insubria and ASST Sette Laghi, Ospedale di
Circolo of Varese, Division of Hematology, Varese, Italy,
35
Oncology
Institute of Southern Switzerland, Clinic of Medical Oncology, Bellin-
zona, Switzerland,
36
Hospital Virgen de la Salud, Division of Pathology,
Toledo, Spain,
37
MD Anderson Cancer Center, Division of Hematology,
Madrid, Spain,
38
University Cancer Center, Inselspital, Department of
Medical Oncology, Bern, Switzerland,
39
Royal Bournemouth Hospital,
Division of Hematology, Bournemouth, UK,
40
University of Insubria
and ASST Sette Laghi, Ospedale di Circolo of Varese, Department of
Medicine and Surgery, Varese, Italy,
41
Ospedale Universitario di
Padova, Division of Hematology, Padova, Italy,
42
Policlinico Uni-
versitario, Division of Pathology, Udine, Italy,
43
S. OrsolaMalpighi
Hospital, University of Bologna, Department of Experimental Diag-
nostic and Specialty Medicine, Bologna, Italy,
44
Université de Lyon,
Faculté de Médecine et de Maïeutique Lyon Sud, Lyon, France,
45
Candiolo Cancer Institute, FPOIRCCS, Division of Hematology,
Candiolo, Italy,
46
Weill Cornell Medical College, Division of Anatomic
Pathology and Clinical Pathology, New York, USA,
47
Hospital Germans
Trias I Pujol, Division of Pathology, Barcelona, Spain,
48
APHP, Hopital
SaintLouis, Hematooncology unit, Paris, France,
49
University Hospitals
Leuven, Department of Haematology, Leuven, Belgium,
50
Spedali Civili,
Division of Hematology, Brescia, Italy,
51
University of Verona,
Department of Medicine, Verona, Italy,
52
University Hospital Zurich,
Department of Medical Oncology and Hematology, Zurich, Switzerland,
53
Università di Bologna, Dipartimento di Medicina Specialistica, Diag-
nostica e Sperimentale, Bologna, Italy,
54
Rutgers University, Center for
Systems and Computational Biology, New Brunswick, USA,
55
Columbia
University, Department of Pathology and Cell Biology, New York, USA,
56
Institut universitaire de pathologie, Division of Pathology, Lausanne,
Switzerland,
57
University Hospital Basel, Institute of Pathology and
Medical Genetics, Basel, Switzerland,
58
European Institute of Oncology
SUPPLEMENT ABSTRACTS
-
81
IRCCS, Haematopathology Division, Milan, Italy,
59
Fundación Jiménez
Díaz, Pathology Service, Madrid, Spain,
60
Centre Hospitalier Lyon Sud,
Division of Pathology, Lyon, France,
61
San Raffaele Scientific Institute,
Ateneo VitaSalute San Raffaele University and Pathology Unit, Milan,
Italy,
62
Cantonal Institute of Pathology, Pathology unit, Locarno,
Switzerland,
63
Institute of Oncology Research, Bellinzona, Switzerland
#
FB, AB, FG equally contributed
*EZ, DR equally contributed
Introduction: Splenic marginal zone Bcell lymphoma (SMZL) is a
heterogeneous entity. The clinical course is variable, mutated genes
are multiple with no unifying mechanism, essential regulatory path-
ways and surrounding microenvironments are diverse. We sought to
provide a unifying view of SMZL by resolving its heterogeneity in
subgroups sharing genomic abnormalities, pathway signatures and
microenvironment compositions to uncover biomarkers and thera-
peutic vulnerabilities.
Methods: We studied 303 pathologically confirmed SMZL spleen
samples collected through the IELSG46 multicenter, international
study (NCT02945319). The study cohort was representative of SMZL
in terms of demographics, clinical features and outcome. We carried
out a genetic and phenotypic analysis, defined selforganized signa-
tures, validated them in independent primary tumors metadata and
in genetically modified mouse models, and correlated them with
outcome data.
Results: We identified and validated two prominent and self
aggregating genetic clusters in SMZL, termed NNK (58% of
cases, from NFkB, NOTCH and KLF2 modules) and DMT (32% of
cases, from DNAdamage response, MAPK and TLR modules).
NNKSMZLs were dominated by mutations of NF‐κB (e.g.,
TNFAIP3, TRAF3, BIRC3), NOTCH (e.g., NOTCH2, NOTCH1,
SPEN) and KLF2. DMTSMZLs were characterized by mutations in
DNA damage response pathway genes (e.g., TP53, ATM). Muta-
tions in MAPK (e.g., BRAF) and TLR genes (e.g., MYD88, all
involving positions other than p.L265) were also enriched in DMT
SMZLs (Figure A and B). These genetic clusters have distinct un-
derpinning biology. NNKSMZLs were enriched of IGHV12*04
allele usage and of 7q deletion, while conversely DMTSMZLs were
82
-
SUPPLEMENT ABSTRACTS
depleted of both of them (Figure C). NNKSMZL expressed
significantly higher levels of genes belonging to NOTCH2 pathway
and of genes that are activated by noncanonical NF‐κB tran-
scription factors. Conversely, DMTSMZL had a signature of TP53
and apoptosis impairment (Figure D). Digital cytometry and in situ
profiling segregated two basic types of SMZL immune microenvi-
ronment termed inflamed SMZL (50% of cases, associated with
inflammatory cells and immune checkpoint activation) and non
inflamed SMZL (50% of cases) (Figure E and F). The combination
of molecular and phenotypic profiling allowed to sort out a high
risk clinical subset of patients whose tumor was characterized by
having both NNK genotype and ‘’inflamed’’ microenvironment
(Figure G).
Conclusions: Our study highlights the complexity of SMZL. The
molecular framework provides an evolving understanding of
the pathogenesis of SMZL, and can be regarded as a building
block for further refining the classification of Bcell tumors of the
spleen, and for aiding the development of rationally targeted
treatments.
The research was funded by: Swiss Cancer League, ID 3746, 4395
4660, and 4705, Bern, Switzerland; Research Advisory Board of the
Ente Ospedaliero Cantonale, ABREOC 201922514, Bellinzona,
Switzerland; European Research Council (ERC) Consolidator Grant
CLLCLONE, ID: 772051; Swiss National Science Foundation, ID
320030_169670/1, 310030_192439, 320036_179318, Berne,
Switzerland; Fondazione Ticinese Contro il Cancro; Fondazione
Fidinam, Lugano, Switzerland; Nelia & Amadeo Barletta Foundation,
Lausanne, Switzerland; Fond’Action, Lausanne, Switzerland; The
Leukemia & Lymphoma Society, Translational Research Program, ID
659420, New York; AFRI, Ente Ospedaliero Cantonale, Bellinzona,
Switzerland; Fondazione Dr. Ettore Balli.
Keywords: Diagnostic and Prognostic Biomarkers, Indolent
nonHodgkin lymphoma, Pathology and Classification of Lymphomas
Conflicts of interests pertinent to the abstract
P. Ghia
Honoraria: AbbVie, ArQule/MSD, AstraZeneca, Beigene, Celgene/
Juno(BMS, Gilead, Janssen, Loxo/Lilly, Roche
Research funding: AbbVie, AstraZeneca, Gilead, Janssen, Sunesis
G. Gritti
Consultant or advisory role: Takeda, IQvia, Gilead Sciences
Research funding: Gilead Sciences
Educational grants: Roche, Abbvie, Gilead Sciences, Abbvie
A. Moccia
Consultant or advisory role: Roche, Janssen and Takeda
L. Scarfó
Honoraria: AbbVie, AstraZeneca and Janssen
D. Rossi
Honoraria: AbbVie, AstraZeneca, Janssen
Research funding: AbbVie, AstraZeneca, Janssen
044 |MONOMORPHIC EPITHELIOTROPIC INTESTINAL TCELL
LYMPHOMA (MEITL): CLINICOPATHOLOGICAL ANALYSIS OF A
MULTICENTER EUROPEAN COHORT
D. Cavalieri
1
, O. Tournilhac
1
, E. Missiglia
2
, C. Bonnet
3
, A. Ledoux
Pilon
4
, B. Bisig
2
, A. Cairoli
5
, E. Poullot
6
, V. Fataccioli
7
, M. Parrens
8
,
M. C. Copin
9
, F. Llamas Gutierrez
10
, L. Xerri
11
, C. Bossard
12
, R. De
Wind
13
, F. Drieux
14
, F. Lhomme
15
, A. Daniel
16
, L. ClémentFilliatre
17
,
F. Lemmonier
18
, P. Morel
19
, R. Noël
20
, T. Brotelle
21
, S. Glaisner
22
,
D. Sibon
23
, A. El Yamani
24
, S. Bologna
25
, K. Queru
26
, G. Damaj
27
,
V. Letailleur
28
, B. Villemagne
29
, E. Fleck
30
, E. Dupont
31
, E. Tcherno-
nog
32
, H. Monjanel
33
, V. de Wilde
34
, D. Vallois
2
, P. Gaulard
35
,
L. de Leval
2
1
CHU de ClermontFerrand, Service d'Hematologie Clinique et de
Therapie Cellulaire, ClermontFerrand, France,
2
Lausanne University
Hospital, Lausanne University, Institute of pathology, Lausanne,
Switzerland,
3
CHU Sart Tilman, Department of Hematology, Liège,
Belgium,
4
CHU de ClermontFerrand, Service d'anatomie pathologique,
ClermontFerrand, France,
5
Lausanne University hospital, Lausanne
University, Service of Hematology, Department of Oncology, Lausanne,
Switzerland,
6
Hôpitaux Universitaires Henri Mondor, APHP, Departe-
ment de Pathologie, France,
7
Université Paris Est Créteil, INSERM,
Institut Médical de Recherche Biomédicale, Créteil, France,
8
CHU de
Bordeaux, Service d'anatomie pathologique, Bordeaux, France,
9
CHU de
Lille, Service d'anatomie pathologique, Lille, France,
10
CHU de Rennes,
Service d'anatomie pathologique, Rennes, France,
11
Institut Paoli
Calmettes, Service d'anatomie pathologique, Marseille, France,
12
CHU
de Nantes, Service d'anatomie pathologique, Nantes, France,
13
Institut
Jules Bordet, Université libre de Bruxelles, Department of pathology,
Bruxelles, Belgium,
14
Centre Henri Becquerel, Service d'anatomie
pathologique, Rouen, France,
15
CHU de Rennes, Service d'hématologie
clinique, Rennes, France,
16
CHU de Lille, Service d'hématologie clinique,
Lille, France,
17
CHRU Nancy, Service d'hématologie clinique, Nancy,
France,
18
Hôpitaux Universitaires Henri Mondor, APHP, Université Paris
EstCréteil, Unité Hémopathies Lymphoïdes, INSERMU955, Créteil,
France,
19
CHU d'Amiens, Service d'hématologie clinique, Amiens,
France,
20
Institut Paoli Calmettes, Service d'hématologie clinique,
Marseille, France,
21
CH d'Avignon, Service d'hématologie clinique,
Avignon, France,
22
Institut CurieHôpital René Huguenin, Service
d'hématologie clinique, SaintCloud, France,
23
Necker University Hos-
pital, APHP, Paris Descartes University Sorbonne Paris Cité, Hema-
tology department, Paris, France,
24
CH de Blois, Service d'hématologie
clinique, Blois, France,
25
Clinique Louis Pasteur, Service d'oncologie,
EsseyLèsNancy, France,
26
CHU de Limoges, Service d'hématologie
clinique, Limoges, France,
27
Institut d'Hématologie de BasseNormandie,
Service d'hématologie clinique, Caen, France,
28
CHU de Nantes, Service
d'hématologie clinique, Nantes, France,
29
CHD Vendée, Service d'hém-
atologie clinique, LaRocheSurYon, France,
30
GH Littoral Atlantique,
Service d'oncologie, La Rochelle, France,
31
CH AgenNerac, Service de
médecine interne, Agen, France,
32
CHU de Montpellier, Service d'hém-
atologie clinique, Montpellier, France,
33
CH d'Aurillac, Service d'héma-
tologie clinique, Aurillac, France,
34
Hôpital Erasme, Hematology
SUPPLEMENT ABSTRACTS
-
83
department, Bruxelles, Belgium,
35
Hôpitaux universitaires Henri Mon-
dor, APHP, Université Paris EstCréteil, Département de pathologie,
INSERMU955, Créteil, France
Introduction: Monomorphic epitheliotropic intestinal Tcell lym-
phoma (MEITL) is a rare aggressive primary intestinal Tcell lym-
phoma. Most case series were reported in Asia. Here we present a
detailed clinicopathological analysis of a European cohort.
Methods: Fourtynine patients (pts) diagnosed with MEITL between
2005 and 2020 were retrived from 42 LYSA centers in France,
Belgium and Switzerland. Pathology was reviewed and confirmed in
all cases, complete immunophenotypic profiles were generated, and
mutation status of 27 relevant genes was obtained by targeted or
whole exome sequencing in 44 cases. Clinical, imaging, and survival
data were collected.
Results: Median age was 69y (2991), 55% were men.
Among 34 pts with anamnestic information: one carried a diagnosis
of coeliac disease, screening for coeliac disease was negative in 12/12
pts tested. 30 pts (88%), presented with abdominal emergency
(bowel perforation n =23 and/or obstruction n =11). B symptoms,
cytopenia and inflammation were found in 65% (n =22), 41% (n =14)
and 94% (n =32). FDGPET/CT showed hypermetabolic lesions with
a high SUVmax (8 to 30).
On the whole cohort of 49 pts : intestinal involvement distribution
was small bowel (n =47), large bowel (n =7), anal (n =1) and
stomach (n =1). Multifocal intestinal involvement was seen in 9 pts.
The Ann Arbor stage was I E (n =15), II E (n =11), and IV (n =15),
missing data (MD) (n =8).
In the 49 pts, the phenotype was CD2+(51%) CD3+(98%) CD4
(94%) CD5(96%) CD7+(98%) CD8+(88%) CD56+(90%) CD103+
(91%) CD79a(90%) EBER(98%) with activated cytotoxic profile.
CD30 and aberrant CD20 expression were detected in 0% and 23%.
TCR was γδ (n =20), αβ(n =5), double positive (n =5) or double
negative (n =11).
SETD2 was mutated (n =38), deleted (n =9) or both (n =6) and 38/
42 showed defective H3K36 trimethylation. Other frequent muta-
tions included STAT5B (n =27), JAK3 (n =22), TP53 (n =14).
A 1
st
line chemotherapy (CT) was recorded in 28 pts including 24
CHOPlike and 4 autologous transplant, 15 did not receive any CT
(MD =9). Following 1
st
line, 9 pts reached a CR, and 13 had primary
progression or insufficient response (MD =6). All salvaged pts
eventually died from progression or toxicity.
Among 48 pts with available followup, median OS was 6m (066). In
the 28 pts receiving CT, median OS was 11m (366) and 3y OS was
13%. Single or double hit mutations for TP53 and STAT5B were
associated with a worse outcome compared to wildtype pts (p =
0,004).
Conclusion: In this large European cohort of MEITL, we expand the
extremely poor prognosis related both to the complexity of clinical
presentation and to primary resistance to CHOPlike poly-
chemotherapy, with a negative impact of single and doublehit mu-
tations of TP53 and STAT5B. Dynamic management including post
operative supportive care, chemotherapy attempt and potential
consolidation by autoor even allograft is crucial.
Keywords: Aggressive Tcell nonHodgkin lymphoma
No conflicts of interests pertinent to the abstract.
045 |RHOA G17V POTENTIATES CD28 T195P MUTATION
INDUCED NFAT TRANSCRIPTIONAL ACTIVITY UPON CD3/CD28
STIMULATION
D. Vallois
1
, E. Missiaglia
1
, B. Bisig
1
, Mél. Favre Juilland
2
, M. Thome
Miazza
2
, L. de Leval
1
1
Lausanne University Hospital and Lausanne University, Institute of
Pathology, Lausanne, Switzerland,
2
Lausanne University, Department of
Biochemistry, Epalinges, Switzerland
Introduction: Recurrent mutations in epigenetic modifiers, RHOA and
other genes related to Tcell receptor (TCR) signaling are found in a
large proportion of angioimmunoblastic Tcell lymphoma and other
lymphomas derived from follicular Thelper cells. After RHOA G17V
mutation found in 6070% of AITL, CD28 is the most commonly
mutated TCRrelated gene (15%). Since CD28 point mutations co
occur with RHOA G17V alteration, we intend to elucidate the po-
tential cooperation of RHOA G17V and CD28 mutations in sustaining
Tcell proliferation.
84
-
SUPPLEMENT ABSTRACTS
Methods: Five stable Jurkat cell lines bearing the two empty vectors
or expressing either RHOA WT or G17V mutant and CD28 WT or
T195P mutant were generated by lentiviral infection and positive
FACS sorting for GFP (RHOA selection) and CD28 expression at the
plasma membrane. We sought for RHOA G17V partners performing
coimmunoprecipitation experiments with Jurkat cells expressing
empty vector or different RHOA variants (WT, G17V and K18N)
followed by mass spectrometry.
Results: The presence of RHOA G17V and CD28 T195P mutants
induced significantly higher levels of IL2 secretion and IL2tran-
scription than either mutant alone upon CD3/CD28 stimulation,
suggesting a synergistic effect. First, we sought for changes in
phosphorylation of key TCR cytoplasmic transductors upon CD3/
CD28 stimulation. Similar phosphorylation levels were found in
cells harboring both mutants versus CD28 mutant alone. Then we
addressed the activity of NFkB, NFAT and AP1 transcription
factors. Luciferase assays showed a significant increase of the
transcriptional activity of NFAT and, to a lesser extent, AP1 fac-
tors, in cells harboring both mutants versus either mutant alone.
Thus, in this model the cooperation of RHOA and CD28 mutants
on increased IL2 secretion does not involve increased phosphory-
lation of TCR signaling molecules, but an increased NFAT and AP1
transcription activity. We then searched for RHOA G17V partners
that could explain our observations. Coimmunoprecipitation anal-
ysis identified about 20 interactors specifically associating to
RHOA G17V, among which those most abundant were VAV1 and
the acetyl transferase P300. NFAT luciferase experiments were
conducted with either VAV1 siRNA or P300dependent NFAT
transactivation inhibition by expressing the E1A viral protein.
Both VAV1 siRNA and P300 inhibition induced a decreased
NFAT transactivation in cells expressing either mutants alone or
both. Moreover, P300 inhibition by the small molecule A485
abolished the increased IL2 secretion induced by CD3/CD28
stimulation in cells transfected with RHOA G17V, CD28 T195P, or
both.
Conclusion: Our results suggest that RHOA G17V expression does
not involve increased phosphorylation of TCR signaling molecules but
rather potentiates CD28 T195Pincreased NFAT transactivation
through VAV1 and P300 activities modulation, leading to a syner-
gistic IL2 secretion.
The research was funded by: FNS Grant 310030_172954
Keywords: Tumor Biology and Heterogeneity, Aggressive Tcell non
Hodgkin lymphoma
No conflicts of interests pertinent to the abstract.
SESSION 7: AGGRESSIVE EXTRANODAL ENTITIES
046 |NONINVASIVE DETECTION, CLASSIFICATION, AND RISK
STRATIFICATION OF PRIMARY CNS LYMPHOMAS BY CTDNA
PROFILING
J. A. Mutter
1
, S. Alig
2
, E. M. Lauer
1
, M. S. Esfahani
2
, J. Mitschke
1
,
D. M. Kurtz
2
, M. Olsen
2
, C. L. Liu
2
, M. C. Jin
2
, S. Bleul
1
,
C. W. Macaulay
2
, N. N. Neidert
3
, D. H. Heiland
3
, J. Finke
1
, J. Duyster
1
,
J. Wehrle
1
, M. Prinz
4
, G. Illerhaus
5
, P. C. Reinacher
6
, E. Schorb
1
,
M. Diehn
7
, A. A. Alizadeh
2
, F. Scherer
1
SUPPLEMENT ABSTRACTS
-
85
1
University Medical Center Freiburg, Department of Hematology,
Oncology, and Stem Cell Transplantation, Freiburg, Germany,
2
Stanford
University, Division of Oncology, Department of Medicine, Stanford,
California, USA,
3
University Medical Center Freiburg, Department of
Neurosurgery, Freiburg, Germany,
4
University Medical Center Freiburg,
Institute of Neuropathology, Freiburg, Germany,
5
Klinikum Stuttgart,
Department of Hematology/Oncology and Palliative Care, Stuttgart,
Germany,
6
University Medical Center Freiburg, Department of
Stereotactic and Functional Neurosurgery, Freiburg, Germany,
7
Stanford
University, Department of Radiation Oncology, Stanford, California,
USA
Introduction: Circulating tumor DNA (ctDNA) has great potential as
a noninvasive biomarker in diverse systemic lymphomas (Huet et al, J
Clin Oncol 2020). Noninvasive access to tumorderived DNA is
particularly appealing for patients with primary CNS lymphoma
(PCNSL), since tumor material otherwise requires invasive surgical
procedures. Here, we explored the value of ctDNA in PCNSL patients
for disease classification, MRD detection, and early prediction of
relapse.
Methods: We applied Cancer Personalized Profiling by Deep
Sequencing (CAPPSeq) to 65 tumor biopsies, 101 blood plasma
specimens, and 43 cerebrospinal fluid (CSF) samples from 68 subjects
with PCNSL, targeting 580 distinct genomic regions. We separately
used Phased variant Enrichment Sequencing (PhasEDSeq, Kurtz
et al, Nat Biotech 2021; in press) for ultrasensitive ctDNA monitoring.
Levels of ctDNA were correlated with radiological measures of tumor
burden and tested for associations with clinical outcomes. Finally, we
developed a novel machine learning classifier to noninvasively
distinguish CNS lymphomas from other CNS tumors based on their
mutation patterns in plasma and CSF, using supervised training of a
random forest followed by its independent validation.
Results: We identified genetic aberrations in 100% of PCNSL tu-
mor specimens (n =65), with a median of 378 mutations per
FIGURE 1 (A) Sensitivity and specificity of ctDNA monitoring in blood plasma and CSF using PhasEDSeq. Grey bars on the left:
sensitivities copmpared to previous NGSbased technologies (Fontanilles et al., Oncotarget 2017, Yoont et al., ASH Annual Meeting 2019,
MontesinosRongen et al., J Mol Diagn 2020, Hattori et al., Cancer Sci 2018). Grey bars on the right show sensitivities of flow cytometry (FC)
and Cytopathology (CP) in our cohort. (B) Scatter plot showing the comparision of ctDNA concentrations in pretreatment blood plasma and
CSF. (C) Correlation of Association between pretreatment ctDNA plasma concentrations and total radiographic tumor volume (TRTV)
measured by MRI. (D) ctDNA concentrations and steroid treatment at blood draw. (F) Kaplan Meier analysis of PFS and OS in patients with
detactabe and nondetectable pretreatment ctDNA at diagnosis or progression. (G) Kaplan Meier analysis of PFS in patients with positive or
negative ctDNA during curative intent induction treatment
86
-
SUPPLEMENT ABSTRACTS
patient. Pretreatment plasma ctDNA was detectable in 82% of
patients and in 100% of CSF samples (Fig. 1A), with ctDNA con-
centrations ranging from 0.0131038 hGE/mL (median: 0.97) in
plasma and 0.0434342 hGE/mL (median: 3.55) in CSF (Fig. 1B).
While ctDNA levels were significantly correlated with total tumor
volume in MRI (p =0.004, Fig. 1C), we did not observe significant
associations between ctDNA levels and MSKCC score or concur-
rent steroid treatment (Fig. 1DE). Pretreatment ctDNA was
significantly associated with PFS (p =0.0005, HR 3.6) and OS (p =
0.019, HR 3.1), both as continuous and binary variable (Fig. 1F).
Furthermore, ctDNA positivity during curative intent induction
therapy accurately predicted clinical outcomes (Fig. 1G). Finally, we
applied our novel machine learning classifier to 129 specimens
from an independent validation cohort. We observed high speci-
ficity (100%) and positive predictive value (100%) for noninvasive
diagnosis of CNSL, with moderate sensitivity (50% for CSF, 20%
for plasma), suggesting that a significant subset of CNSL patients
might be able to forego invasive biopsies.
Conclusions: We demonstrate robust and ultrasensitive detection of
ctDNA at various disease milestones in PCNSL. Our findings suggest
that ctDNA could serve as a valuable clinical biomarker for tumor
burden assessment, outcome prediction, and biopsyfree lymphoma
classification. We envision an important future role of ctDNA for
personalized risk stratification and guiding therapies in clinical trials
and in routine PCNSL management.
The research was funded by: the Else KrönerFreseniusStiftung (to
FS, 2018_A83), the Fördergesellschaft Forschung Tumorbiologie (to
FS), and the Clinician Scientist Program of the Deutsche Gesellschaft
für Innere Medizin (to FS)
Keywords: Diagnostic and Prognostic Biomarkers, Liquid biopsy,
Extranodal nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
D. M. Kurtz
Consultant or advisory role: Roche Molecular Diagnostics,
Genentech
Other remuneration: Ownership equity in Foresight Diagnostics. Dr.
Kurtz has patents pending related to methods for analysis of cell free
nucleic acids and methods for treatment selection based on statistical
frameworks of clinical outcome.
M. Diehn
Consultant or advisory role: Roche, AstraZeneca, RefleXion and
BioNTech
Research funding: Varian Medical Systems, Illumina
Other remuneration: Ownership interest in CiberMed, patent filings
related to cancer biomarkers
A. A. Alizadeh
Consultant or advisory role: Genentech, Roche, Chugai, Gilead,
Celgene
Other remuneration: Ownership interest in CiberMed and FortyS-
even Inc, patent filings related to cancer biomarkers.
047 |MATRIX INDUCTION FOLLOWED BY AUTOLOGOUS
STEM CELL TRANSPLANT OR WHOLEBRAIN IRRADIATION IN
PRIMARY CNS LYMPHOMA. 7YEAR RESULTS OF THE IELSG32
RANDOMIZED TRIAL
A. J. M. Ferreri
1
, K. Cwynarski
2
, E. Jacobsen Pulczynski
3
, C. Fox
4
,
E. Schorb
5
, C. Celico
6
, M. Falautano
7
, A. Nonis
8
, P. La Rosée
9
,
M. Binder
10
, A. Fabbri
11
, F. Ilariucci
12
, M. Krampera
13
, A. Röth
14
,
C. Hemmaway
15
, P. W. Johnson
16
, K. M. Linton
17
, T. Pukrop
18
,
J. Sønderskov Gørløv
19
, M. Balzarotti
20
, G. Hess
21
, U. Keller
22
,
S. Stilgenbauer
23
, J. Panse
24
, A. Tucci
25
, L. Orsucci
26
, F. Pisani
27
,
M. Zanni
28
, S. Krause
29
, H. J. Schmoll
30
, B. Hertenstein
31
,
M. Rummel
32
, J. Smith
33
, L. Thurner
34
, M. G. Cabras
35
, E. Pennese
36
,
M. Ponzoni
37
, M. Deckert
38
, L. S. Politi
39
, Jür. Finke
40
, A. Ferranti
41
,
K. Cozens
42
, E. Burger
43
, N. Ielmini
44
, F. Cavalli
44
, E. Zucca
45
,
G. Illerhaus
46
1
IRCCS San Raffaele Scientific Institute, Unità Operativa di Oncologia
Medica, Milano, Italy,
2
University College London Hospitals NHS Trust,
Department Of Haematology Royal Free Hospital, London, UK,
3
Aarhus
University Hospital, Department of Haematology, Aarhus, Denmark,
4
Nottingham University Hospitals NHS Trust, Clinical Haematology City
Campus, Nottingham, UK,
5
Universitätsklinikum Freiburg, Klinik für
INnere Medizin I, Freiburg, Germany,
6
IRCCS San Raffaele Scientific
Institute, Unità di Neuroriabilitazione, Milano, Italy,
7
IRCCS San Raffaele
Scientific Institute, Institute of Experimental Neurology, Milano, Italy,
8
IRCCS San Raffaele Scientific Institute, University Centre for Statistics in
the Biomedical Sciences, Milano, Italy,
9
SchwarzwaldBaar Klinikum, Kli-
nik für Innere Medizin II, VillingenSchwenningen, Germany,
10
Uni-
versitätskrankenhaus HamburgEppendorf UKE, Zentrum für Onkologie,
Hamburg, Germany,
11
Azienda Ospedaliera Universitaria Senese, UOC
Ematologia e Trapianti, Siena, Italy,
12
Azienda Ospedaliera di Reggio
Emilia, Arcispedale Santa Maria Nuova Ematologia, Reggio Emilia, Italy,
13
Policlinico G.B. Rossi, Divisione di Ematologia, Verona, Italy,
14
Uni-
versitätsmedizin Essen, Westdeutsches Tumorzentrum Essen, Essen, Ger-
many,
15
Queen's Hospital, Hematology, Romford, UK,
16
Cancer Research
UK Centre, Southampton General Hospital, Southampton, UK,
17
Univer-
sity of Manchester, The Christie NHS Foundation Trust, Manchester, UK,
18
GeorgAugustUniversität Göttingen, Hämatologie und Oncologie, Göt-
tingen, Germany,
19
Rigshospitalet, Department of Hematology 4042,
Copenhagen, Sweden,
20
Istituto Clinico Humanitas, U.O. Oncologia
Medica ed Ematologia, Milano Rozzano, Italy,
21
Universitätsmedizin
Mainz, III Medizinische Klinik und Poliklinik, Mainz, Germany,
22
Techni-
sche Universität München, III. Medizinischen Klinik des Klinikums rechts
der Isar, München, Germany,
23
Universitätsklinikum Ulm, Klinik für innere
Medizin, Ulm, Germany,
24
Universitätsklinikum Aachen, Klinik für Innere
Medizin IV Hämatologie/Onkologie, Aachen, Germany,
25
Spedali Civili,
SC Ematologia, Brescia, Italy,
26
A.O.U. Città della Salute e della Scienza di
Torino, Dipartimento di Oncologia ed Ematologia, Torino, Italy,
27
Istituto
Regina Elena, SC Ematologia, Roma, Italy,
28
Azienda Ospedaliera Nazio-
nale SS. Antonio e Biagio e C. Arrigo, SC Ematologia, Alessandria, Italy,
29
Universitätsklinikum Erlangen, Medizinische Klinik 5, Erlangen, Ger-
many,
30
MartinLuther Universität, Klinik für Hämatologie/Onkologie,
SUPPLEMENT ABSTRACTS
-
87
Halle, Germany,
31
Klinikum BremenMitte GmbH, Medizinische Klinik I,
Bremen, Germany,
32
Klinikum der JustusLiebingUniversität, Klinikum
der JustusLiebingUniversität Medizinische Klinik IV, Giessen, Germany,
33
Aintree University Hospital NHS FoundationTrust, Hematology, Liver-
pool, UK,
34
Universitätsklinikum des Saarlandes, Innere Medizin I, Hom-
burg, Germany,
35
Ospedale A. Businco, Unità Operativa di Ematologia,
Cagliari, Italy,
36
Presidio Ospedaliero Spirito Santo, Centro diagnosi e
terapia dei linfomi, Pescara, Italy,
37
IRCCS San Raffaele Scientific Insti-
tute, Haematopathology Diagnostic Area, Milano, Italy,
38
University of
Cologne, Department of Neuropathology, Köln, Germany,
39
IRCCS San
Raffaele Scientific Institute, Neuroradiology research, Milano, Italy,
40
Universitätsklinikum Freiburg, Klinik für Innere Medizin I, Freiburg,
Germany,
41
Fondazione Italiana Linfomi, Alessandria, Italy,
42
University
of Southampton, Clinical Trials Unit, Southampton, UK,
43
Uni-
versitätsklinikum Freiburg, Projektkoordination Klinische Studien, Frei-
burg, Germany,
44
Foundation for the Institute of Oncology Research (IOR),
International Extranodal Lymphoma Study Group, Bellinzona, Switzerland,
45
Foundation for the Institute of Oncology Research (IOR), International
Extranodal Lymphoma Study Group, Oncology Institute of Southern
Switzerland, Medical Oncology Clinic, Bellinzona, Switzerland,
46
Stuttgart
Cancer Centre (SCC), Clinic for Hematology and Internistisc Oncology,
Stuttgart, Germany
Introduction: The MATRix regimen (methotrexate, cytarabine, thio-
tepa, rituximab) significantly improved outcome of patients (pts) with
primary CNS lymphoma (PCNSL) enrolled in the IELSG32 trial. At a
median followup of 40 months, both wholebrain irradiation (WBRT)
and autologous transplantation (ASCT) resulted in similar
progressionfree survival (PFS) rates. Sound assessment of overall
survival (OS), late complications, incidence of secondary tumors, and
cognitive impairment require, however, longer followup. Herein, we
report the results of this trial at a median followup of 88 (IQR 7799)
months.
Methods: HIVnegative pts aged 1870 years with newly diagnosed
PCNSL were randomly assigned to receive 4 courses of
methotrexatecytarabine (arm A), or arm A plus rituximab (arm B), or
arm B plus thiotepa (MATRix; arm C). A second randomization allo-
cated pts with responsive/stable disease to WBRT (arm D) or car-
mustine thiotepa conditioning followed by ASCT (arm E). Treatment
effect on cognitive functions and quality of life (QoL) was addressed
using the IPCG tests panel and EORTCQLQ.
Results: 219 assessable pts were randomized (arm A 75; B 69; C
75). After induction, 167 had responsive or stable disease; 118
were assigned to WBRT (59) or ASCT (59) while 49 were excluded
from second randomization (poor mobilizers, poor conditions,
refusal). Fifteen pts died of toxicity during treatment. Of 87 (40%)
relapsefree pts (A 17; B 28; C 42), 14 died of infections (4),
sudden death (4), cognitive decline (3), second tumor (2) and car
accident (1). Among 117 pts with relapse, 96 died of lymphoma, 7
died of salvage therapy complications. Eight pts developed second
cancers 4896 months after WBRT (5) or ASCT (3). Second tumors,
deaths in relapsefree pts and deaths during salvage therapy were
not significantly related to induction or consolidation treatments.
Neuropsychological tests showed a statistically significant impair-
ment in attentiveness and executive functions in pts treated with
WBRT, while transplanted pts had a significant improvement in
these functions as well as in memory and QoL. Pts treated with
MATRix (arm C) showed significantly better PFS (7year: 52% vs
20% for arm A; vs 29% for arm B) and OS rates (7year: 56% vs
26% for arm A; vs 37% for arm B). No significant difference was
seen between the consolidation arms for either PFS (7year: 55%
for arm D vs 50% for arm E) or OS (7year: 63% vs 57%). Pts
treated with MATRix induction and consolidation had a 7year OS
of 70%, without a significant difference between WBRT and ASCT.
IELSG score, number of lesions and induction arm were indepen-
dent predictors of OS.
Conclusions: MATRix regimen was associated with an excellent long
term outcome. WBRT and ASCT had comparable efficacy. MATRix
and ASCT did not result in higher nonrelapse mortality or second
tumors incidence in comparison to the other study arms, whereas
WBRT led to impairment of specific cognitive functions.
EA previously submitted to EHA 2021.
The research was funded by: IELSG32 was supported in part by
grants from Agenzia Italiana del Farmaco (Ricerca Indipendente
FARM99FS3Y), Oncosuisse (KLS 02399022009), Swiss National
Science Foundation (31003B_132924) and Cancer Research UK
C36711/A12115). Adienne kindly supplied thiotepa for the treat-
ment of patients registered in the UK
88
-
SUPPLEMENT ABSTRACTS
Keywords: Chemotherapy Combination, Therapies Immunotherapy
Conflicts of interests pertinent to the abstract
A. J. M. Ferreri
Consultant or advisory role: Adienne, Gilead, Novartis, Juno,
PLetixaPharm
Research funding: BMS, Beigine, Pharmacyclics, Hutchison Medi-
pharma, Amgen, Genmab, ADC Therapeutics, Gilead, Novartis,
Pfizer
K. Cwynarski
Consultant or advisory role: Roche
Honoraria: Roche
Educational grants: Roche
E. Jacobsen Pulczynski
Research funding: Roche
C. Fox
Consultant or advisory role: Abbvie, AstraZeneca, Atarabio, BMS/
Celgene, Gilead, Jansen, Incyte, Roche, Takeda
Honoraria: Abbvie, Atarabio, BMS/Celgene, Jansen, Incyte, Roche,
Takeda
Research funding: Abbvie, Gilead, Roche, Takeda
Educational grants: Abbvie, BMS/Celgene, Janssen, Roche, Takeda
E. Schorb
Honoraria: Riemser Pharma GmbH
Research funding: Riemser Pharma GmbH
K. M. Linton
Consultant or advisory role: Genmab Celgene Kite/Gilead
Honoraria: Janssen
Research funding: Roche Karyopharm
Educational grants: Janssen
U. Keller
Consultant or advisory role: Roche
Educational grants: Roche
S. Stilgenbauer
Consultant or advisory role: AbbVie, Amgen., AstraZeneca, Celgene,
Gilead, GSK, HoffmannLaRoche, Janssen, Novartis
Honoraria: AbbVie, Amgen., AstraZeneca, Celgene, Gilead, GSK,
HoffmannLaRoche, Janssen, Novartis
Research funding: AbbVie, Amgen., AstraZeneca, Celgene, Gilead,
GSK, HoffmannLaRoche, Janssen, Novartis
J. Smith
Educational grants: Grant provided to attend 15ICML by Janssen,
but arranged by Janssen (no payment)
L. Thurner
Consultant or advisory role: Merck, EUSAPharma, Takeda
Educational grants: EUSAPharma, Janssen, Abbvie
J. Finke
Honoraria: Riemser
Research funding: Riemser
G. Illerhaus
Honoraria: Riemser
Educational grants: Riemser
048 |INTENSIFIED (INTRAVENOUS AND INTRATHECAL) CNS
PROPHYLAXIS IN PRIMARY TESTICULAR DIFFUSE LARGE BCELL
LYMPHOMA: 5YEAR RESULTS OF THE IELSG30 TRIAL
A. Conconi
1
, A. Chiappella
2
, L. Orsucci
2
, G. Gaidano
3
, Andrés J.M.
Ferreri
4
, M. Balzarotti
5
, A. Tucci
6
, B. Botto
2
, A. Moccia
7
, A. Vanazzi
8
,
F. Merli
9
, M. Tani
10
, F. Esposito
11
, L. Bonomini
12
, U. Vitolo
13
,
E. Zucca
11
1
Azienda sanitaria locale Biella, Ospedale degli Infermi Ematologia,
Biella, Italy,
2
A.O.U. Città della Salute e della Scienza di Torino,
Dipartimento di Oncologia ed Ematologia, Torino, Italy,
3
Azienda
Ospedaliera "Maggiore della Carità", Ematologia, Novara, Italy,
4
IRCCS
San Raffaele Scientific Institute, Unità Operativa di Oncologia Medica,
Milano, Italy,
5
Istituto Clinico Humanitas, U.O. Oncologia Medica ed
Ematologia, Milano Rozzano, Italy,
6
Spedali Civili, SC Ematologia, Brescia,
Italy,
7
Oncology Institute of Southern Switzerland, Medical Oncology
Clinic, Bellinzona, Switzerland,
8
Istituto Europeo di Oncologia,
Oncoematologia, Milano, Italy,
9
Azienda Ospedaliera di Reggio Emilia,
Arcispedale Santa Maria Nuova Ematologia, Reggio Emilia, Italy,
10
Ospedale Santa Maria delle Croci, Dipartimento di Oncologia ed
Ematologia, Ravenna, Italy,
11
Foundation for the Institute of Oncology
Research (IOR), International Extranodal Lymphoma Study Group,
Oncology Institute of Southern Switzerland, Medical Oncology Clinic,
Bellinzona, Switzerland,
12
Foundation for the Institute of Oncology
Research (IOR), International Extranodal Lymphoma Study Group,
Bellinzona, Switzerland,
13
Candiolo Cancer Institute FPOIRCCS, Onco-
logia Medica, Candiolo, Italy
Introduction: Primary diffuse large Bcell lymphoma of the testis
(PTL) represents a unique condition characterized by high long
term risk of contralateral testis and central nervous system
(CNS) relapse (>30% at 15 years) in historical series (Zucca et al,
JCO 2002). Immunochemotherapy associated with intrathecal CNS
prophylaxis and contralateral testis radiotherapy (RT) improved
patient outcome, with a virtual elimination of contralateral re-
currences and significant reduction (6% at 5 years) of CNS re-
lapses in the IELSG10 trial (Vitolo et al., JCO 2011). The
International Extranodal Lymphoma Study Group (IELSG), in
cooperation with the Italian Lymphoma Foundation (FIL), coordi-
nated the multicenter phase II IELSG30 study to assess activity
and feasibility of intensified CNS prophylaxis in combination with
chemoimmunotherapy and RT.
SUPPLEMENT ABSTRACTS
-
89
Patients and Methods: Patients with stage III PTL were eligible.
Treatment consisted of 6 cycles of the standard RCHOP21
regimen (rituximab, cyclophosphamide, doxorubicin, vincristine
and prednisone every 21 days); 4 doses of intrathecal liposomal
cytarabine; 2 courses of intravenous (iv) intermediatedose meth-
otrexate (1.5 gr/m2) and RT (2530 Gy) to the contralateral testis.
The study was designed to demonstrate (80% power, a =.05) a
PFS improvement from 67% to 82% at 10 years (primary
endpoint).
Results: Fiftyfour patients (median age: 66 years, range: 3779
years) with untreated stage I (n =32) or II (n =22) PTL were
treated with RCHOP21, 53 received at least 3 doses of intra-
thecal CNS prophylaxis, 48 received at least one dose of iv
methotrexate and 50 received prophylactic RT. No unexpected
side effects were observed. At a median followup of 5 years, 7
patients progressed and 7 died, with 5year PFS of 88% (95%CI,
7494%) and 5year OS of 92% (95%CI, 79%97%). No CNS re-
lapses occurred. In 4 cases, both nodal and extranodal relapses
were reported, the latter including the gastrointestinal tract and
the pleurae in the same patient, as well as, 1 patient each, the
kidneys, the spinal canal (extraaxial) and the contralateral testis (9
years after RT). Two patients relapsed only at extranodal sites
(skin, adrenal gland), 1 had nodal relapse. Notably, 4 of 7 failures
were late relapses occurring after 6 to 10 years from treatment.
Causes of death were lymphoma (n =4), second cancer (n =1),
cerebral vasculopathy (n =1), unknown (n =1).
Conclusions: Definitive assessment of the primary endpoint will need
longer followup. Thus far, comparison of these results with those of
the IELSG10 trial (5yr PFS, 88 vs 74%; 5yr OS, 92 vs 85%; 5yr CNS
relapse rate, 0 vs 6%) suggests that combined treatment of PTL with
RCHOP21 plus intensive CNS prophylaxis and locoregional RT is
feasible, may abrogate CNS relapses and lead to very promising
outcomes. Nevertheless, late relapses, mainly at extranodal sites, still
represent a clinical challenge.
The research was funded by: Mundipharma provided the drug
depocyte free of charge
Keywords: Combination Therapies, Radiation Therapy
Conflicts of interests pertinent to the abstract
A. J. M. Ferreri
Consultant or advisory role: Adienne Gilead Novartis Juno
PletixaPharm
Research funding: BMS Beigene Pharmacyclics Hutchison
Medipharma Amgen Genmab ADC Therapeutics Gilead
Novartis Pfizer
E. Zucca
Consultant or advisory role: Beigene Celgene Incyte Janssen
Merck Roche Celltrion Healthcare Kite (Gilead)
Research funding: AstraZeneca Celgene Incyte Janssen Merck
Roche
Educational grants: Roche Abbvie
049 |IMPACT OF DIFFERENT INDUCTION REGIMENS ON THE
OUTCOME OF PRIMARY MEDIASTINAL B CELL LYMPHOMA IN
THE PROSPECTIVE IELSG 37 TRIAL
M. Martelli
1
, E. Zucca
2
, B. Botto
3
, I. Kryachok
4
, L. Ceriani
5
,
M. Balzarotti
6
, A. Tucci
7
, M. G. Cabras
8
, V. R. Zilioli
9
, C. Rusconi
9
,
F. Angrilli
10
, L. Arcaini
11
, A. Dabrowska Iwanicka
12
, A. J. M. Ferreri
13
, F.
Merli
14
, W. Zhao
15
, D. Hodgson
16
, C. Ionescu
17
, A. Fosså
18
, K.
Cwynarski
19
, G. Mikhaeel
20
, M. Jerkeman
21
, A. Janikova
22
,
A. Hüttmann
23
, G. Ciccone
24
, U. Metser
16
, S. Barrington
25
,
B. Malkowski
26
, A. Versari
27
, F. Esposito
2
, K. Cozens
28
, N. Ielmini
29
,
U. Ricardi
32
, F. Cavalli
29
, P. Johnson
30
, A. Davies
31
1
Università La Sapienza, Dipartimento Biotecnologie Cellulari ed
Ematologia, Roma, Italy,
2
Foundation for the Institute of Oncology
90
-
SUPPLEMENT ABSTRACTS
Research (IOR), International Extranodal Lymphoma Study Group,
Oncology Institute of Southern Switzerland, Medical Oncology Clinic,
Bellinzona, Switzerland,
3
A.O.U. Città della Salute e della Scienza di
Torino, Dipartimento di Oncologia ed Ematologia, Torino, Italy,
4
National Cancer Institute, Oncohematology, Kyiv, Ukraine,
5
Institute of
Imaging of Southern Switzerland, Department of nuclear medicine and
PET/CT Centre, Lugano, Switzerland,
6
Istituto Clinico Humanitas, U.O.
Oncologia Medica ed Ematologia, Milano Rozzano, Italy,
7
Spedali Civili,
SC Ematologia, Brescia, Italy,
8
Ospedale Oncologico, Struttura
complessa di Ematologia e CTMO, Cagliari, Italy,
9
Azienda Ospedaliera
Ospedale Niguarda Ca’ Granda, Ematologia, Milan, Italy,
10
Lymphoma
Unit, Oncology and Hematology, Pescara, Italy,
11
I.R.C.C.S. Policlinico
San Matteo, Divisione di Ematologia, Pavia, Italy,
12
Maria Sklodowska
Curie Memorial Cancer Center, Department of lymphoid malignancies,
Warsaw, Poland,
13
IRCCS San Raffaele Scientific Institute, Unità
Operativa di Oncologia Medica, Milano, Italy,
14
Arcispedale Santa
Maria Nuova, Servizio di Ematologia, Reggio Emilia, Italy,
15
Rui Jin
Hospital, Hematology, Shanghai, China,
16
University Health Network,
Princess Margaret Hospital, Toronto, Canada,
17
Inselspital, Klinik und
Poliklinik für Medizinische Onkologie, Bern, Switzerland,
18
University
Hospital, Oncology, Oslo, Norway,
19
University College London Hospi-
tals NHS Trust, Department Of Haematology Royal Free Hospital,
London, UK,
20
Guy's & St. Thomas Hospital, Clinical Oncology, London,
UK,
21
University Hospital, Medical Oncology, Lund, Sweden,
22
Univer-
sity Hospital BrnoBohunice, Department of Internal Medicine, Hema-
tology and Oncology, Brno, Czech Republic,
23
Universitatsklinikum
Essen, Hematology, Essen, Germany,
24
AOU Città della Salute e della
Scienza di Torino (Molinette) e CPO, SSD Epidemiologia Clinica e
Valutativa, Torino, Italy,
25
St Thomas' Hospital, Nuclear Medicine,
London, UK,
26
Bydgoszcz Medical Center, Nuclear medicine,
Bydgoszcz1, Poland,
27
Arcispedale S. Maria Nuova, Nuclear Medicine,
Reggio Emilia, Italy,
28
University of Southampton, Clinical Trials Unit,
Southampton, UK,
29
Foundation for the Institute of Oncology Research
(IOR), International Extranodal Lymphoma Study Group, Bellinzona,
Switzerland,
30
Southampton General Hospital, Cancer Research UK
Centre, Southampton, UK,
31
Southampton General Hospital, Cancer
Sciences Division, Southampton, UK,
32
A.O.U. Città della Salute e della
Scienza di Torino, Sezione di Radioterapia, Dipartimento di Oncologia
ed Ematologia, Torino, Italy
Introduction: Primary mediastinal Bcell lymphoma (PMBCL) is
characterized by poor prognosis if adequate responses are not
rapidly achieved or if the disease recurs. Therefore, doseintensive
chemoimmunotherapy regimens are widely used but their superi-
ority over the standard RCHOP21 regimen has not been proven
by randomized trials, furthermore they come with significant
associated toxicities. Radiotherapy (RT) can consolidate responses
after induction, but it may increase the risk of second malignancies
and accelerate coronary heart disease. The IELSG37 trial was
planned according to a noninferiority design to demonstrate that
RT may be unnecessary in patients achieving a metabolic com-
plete remission. The primaryendpoint analysis per arm will be
reported when >80% will have a minimum posttreatment follow
up of 30 months. Herein we present a preliminary analysis of the
outcomes after different induction regimens in the whole study
population.
Methods: Patients with newly diagnosed PMBCL were eligible. Initial
therapy was to be based on a combination containing rituximab and
anthracyclines. The regimen was chosen according to local practice.
Upon central review of postinduction PET scans, responding pa-
tients were randomized to observation versus consolidative RT. Re-
sponses were defined according to the Lugano classification using the
Deauville 5point scale (DS). Patients progressing during induction
did not have central PET review and in the present analysis were
assigned DS score 5.
Results: 545 patients (209 men, 336 women) were enrolled and
treated with RV/MACOPB (n =168, 31%), RCHOP14 (n =146,
27%), RCHOP21 (n =98, 18%), DAEPOCHR (n =88, 16%), R
megaCHOP (n =19, 3%), other doseintensive regimen (n =26,
5%). At a median follow up of 3 years, approx. 95% of patients are
SUPPLEMENT ABSTRACTS
-
91
alive. The rate of complete metabolic responses (CR, defined by DS 1
3) did not differ significantly across regimens, however an unbal-
anced distribution of DS score was evident, apparently due to the
rate of patients with a probable induction failure (DS5) more than 2
times higher for CHOP21 in comparison to the other regimens. At
preliminary univariate analysis there was no significant association of
advanced stage, older age, extranodal infiltration, poor performance
status, bulky disease, unfavorable international prognostic index (IPI)
and larger metabolic tumor volume (MTV) with the use of CHOP21.
Patients receiving DAEPOCHR were somehow younger than the
rest.
Conclusion: Initial regimen may have critical impact on PMBCL
outcome. RCHOP21 appeared inferior to dosedense/doseintensive
regimens.
The research was funded by: IELSG37 was supported in part by
grants from Swiss National Science Foundation (SNSF) Project
32003B_146931,Krebsforschung Schweiz Projec KFS285208
2011 and Cancer Research UK (C30423/A16247)The enrolment of
Swiss patients was supported by the Swiss Group for Clinical Cancer
Research (SAKK)
Keywords: Chemotherapy Combination, Therapies Immunotherapy
No conflicts of interests pertinent to the abstract.
050 |OUTCOMES AFTER FIRSTLINE
IMMUNOCHEMOTHERAPY FOR PRIMARY MEDIASTINAL B CELL
LYMPHOMA PATIENTS: A LYSA STUDY
V. Camus
1
, C. Rossi
2
, P. Sesques
3
, J. Lequesne
4
, D. Tonnelet
5
,
C. Haioun
6
, E. Durot
7
, A. Willaume
8
, M. Gauthier
9
, MarieP. Moles
Moreau
10
, C. Antier
11
, J. Lazarovici
12
, H. Monjanel
13
, S. Bernard
14
,
M. Tardy
15
, C. Besson
16
, L. Lebras
17
, S. Choquet
18
, K. Le Du
19
,
C. Bonnet
20
, S. Bailly
21
, G.L. Damaj
22
, K. Laribi
23
, H. Maisonneuve
24
,
R. Houot
25
, A. Chauchet
26
, F. Jardin
1
, A. TraverseGlehen
27
,
P. Decazes
5
, S. Becker
5
, A. BerrioloRiedinger
28
, H. Tilly
1
1
Centre Henri Becquerel, Department of Hematology, Rouen, France,
2
Dijon University Hospital, Hematology, Dijon, France,
3
CHU Lyon Sud,
Hematology, PierreBénite, France,
4
Centre Henri Becquerel, Clinical
Research Unit, Rouen, France,
5
Centre Henri Becquerel, Department of
Nuclear Medicine, Rouen, France,
6
CHU Mondor, Hematology, Créteil,
France,
7
CHU Reims, Hematology, Reims, France,
8
CHU Lille,
Hematology, Lille, France,
9
IUCT Oncopole, Hematology, Toulouse,
France,
10
CHU Angers, Hematology, Angers, France,
11
CHU Nantes,
Hematology, Nantes, France,
12
Institut Gustave Roussy, Hematology,
Villejuif, France,
13
CH Aurillac, Hematology, Aurillac, France,
14
CHU St
Louis, Hematology, Paris, France,
15
Centre Antoine Lacassagne,
Hematology, Nice, France,
16
Centre Hospitalier de Versailles,
Hematology, Le Chesnay, France,
17
Centre Leon Berard, Hematology,
Lyon, France,
18
CHU La pitié salpetriere, Hematology, Paris, France,
19
Clinique Victor Hugo, Hematology, Le Mans, France,
20
Liege
University Hospital, Hematology, Liege, Belgium,
21
Cliniques
Universitaires Saint Luc, Hematology, Bruxelles, Belgium,
22
CHU Caen,
Hematology, Caen, France,
23
CH Le Mans, Hematology, Le Mans,
France,
24
CH Departemental de Vendée, Hematology, la Roche sur
Yon, France,
25
CHU Rennes, Hematology, Rennes, France,
26
CH
Besançon, hematology, Besançon, France,
27
CHU Lyon Sud,
Pathology, PierreBénite, France,
28
CHU Dijon, Nuclear Medicine,
Dijon, France
Introduction: Primary mediastinal Bcell lymphoma (PMBL) is a
rare subtype of aggressive lymphoma typically affecting young
female patients. The firstline standard of care remains debated.
Methods: We performed a large multicenter retrospective study in
25 centers in France and Belgium to describe PMBL patient out-
comes after firstline treatment in reallife settings. All adult pa-
tients with newly diagnosed PMBL treated in France and Belgium
by participating Lymphoma Study Association (LYSA) centers from
01/01/2007 to 31/12/2017 were identified from local databases.
The inclusion criteria were as follows: firstline treatment with
ACVBP or CHOP plus antiCD20 monoclonal antibody, PET per-
formed at baseline and the patient's nonopposition statement.
Primary endpoint was progressionfree survival (PFS) and second-
ary endpoints included overall survival (OS) and baseline total
metabolic tumor volume (TMTV) using the 41% SUVmax threshold
method.
Results: Three hundred thirteen patients were enrolled and
received rituximab (R) plus ACVBP (n =180) or CHOP delivered
every 14 (RCHOP14, n =76) or 21 days (RCHOP21, n =57)
and consolidation strategies in modalities that varied according to
time and institution, mainly guided by positron emission tomog-
raphy. Consolidation autologous stem cell transplantation was
performed for 46 (25.6%), 24 (31.6%) and one (1.8%) patients in
the RACVBP, RCHOP14 and RCHOP21 groups, respectively (p
<0.001); only 17 (5.4%) patients received mediastinal radio-
therapy. The endoftreatment complete metabolic response rates
were 86.3%, 86.8% and 76.6% (p =0.23) in the RACVBP, R
CHOP14 and RCHOP21 groups, respectively. The median
followup was 44 (1153) months, and the RACVBP, RCHOP14
and RCHOP21 3year PFS and OS were 89.4% (84.894.2%),
89.4% (82.796.6%), and 74.7% (95% CI: 6487.1%), (p =0.018,
Figure 1A), respectively; and 92.4% (88.496.7%), 100% (100
100%), and 87.5% (78.697.6%), (p =0.0036, Figure 1B), respec-
tively. Baseline TMTV360 cm3 was associated with a lower
PFS (hazard ratio =2.18 [1.054.53]). Excess febrile neutropenia
(24.4% vs 5.3% vs 5.3%, p <0.001) and mucositis (22.8% vs 3.9%
vs 1.8%, p <0.001) were observed with RACVBP compared to R
CHOP regimens.
Conclusion: PMBL patients treated with dosedense immunoche-
motherapy without radiotherapy have excellent outcomes. RACVBP
acute toxicity was higher than that of RCHOP14. Our data
confirmed the prognostic importance of the baseline TMTV.
The research was funded by: grants from the Centre Henri Becquerel
and the Ligue Contre le Cancer (Comité de la Manche).
92
-
SUPPLEMENT ABSTRACTS
Keywords: Aggressive Bcell nonHodgkin lymphoma
No conflicts of interests pertinent to the abstract.
051 |NIVOLUMAB PLUS BRENTUXIMAB VEDOTIN FOR
RELAPSED/REFRACTORY PRIMARY MEDIASTINAL LARGE B
CELL LYMPHOMA: EXTENDED FOLLOWUP FROM THE PHASE 2
CHECKMATE 436 STUDY
P. L. Zinzani
1
, A. Santoro
2
, G. Gritti
3
, P. Brice
4
, P. M. Barr
5
,
J. Kuruvilla
6
, D. Cunningham
7
, J. Kline
8
, N. A. Johnson
9
,
N. MehtaShah
10
, M. Fanale
11
, S. Francis
12
, A. J. Moskowitz
13
1
“Seràgnoli" Bologna University, Institute of Hematology, Bologna, Italy,
2
IRCCS Humanitas Research Center, Humanitas University, Rozzano–
Milano, Italy,
3
Ospedale Papa Giovanni XXIII, Hematology and Bone
Marrow Transplant Unit, Bergamo, Italy,
4
Hôpital SaintLouis, Service
d’HématoOncologie, Paris, France,
5
University of Rochester, Depart-
ment of Medicine, Hematology/Oncology, Rochester, New York, USA,
6
Princess Margaret Cancer Centre, Division of Medical Oncology and
Hematology, Toronto, Canada,
7
Royal Marsden Hospital, Gastrointes-
tinal and Lymphoma Unit, London, UK,
8
University of Chicago,
Department of Medicine, Section of Hematology/Oncology, Chicago,
Illinois, USA,
9
Jewish General Hospital, Division of Hematology, Mon-
treal, Canada,
10
Washington University in St. Louis School of Medicine,
Division of Oncology, Department of Medicine, St. Louis, Missouri, USA,
11
Seagen Inc., Medical Affairs, Bothell, Washington, USA,
12
Bristol
Myers Squibb, Global Biometrics and Data Sciences, Princeton, New
Jersey, USA,
13
Memorial Sloan Kettering Cancer Center, Lymphoma
Inpatient Unit, New York, New York, USA
Introduction: Patients (pts) with relapsed/refractory (R/R) pri-
mary mediastinal Bcell lymphoma (PMBL) have poor outcomes
and limited treatment options. PMBL is characterized by
increased programmed death1 (PD1) ligand expression and weak
CD30 expression. The combination of nivolumab (NIVO), an anti–
PD1 immune checkpoint inhibitor, and brentuximab vedotin
(BV), an antiCD30 antibody–drug conjugate, has been assessed
in pts with R/R PMBL in the openlabel, phase 1/2 CheckMate
436 study (NCT02581631); in the primary analysis (median
followup [FU] 11.1 months) NIVO +BV showed an ORR of 73%
and complete remission (CR) rate of 37% (Zinzani et al. J
Clin Oncol 2019). We report efficacy and safety data after
extended FU.
Methods: The expansion cohort of CheckMate 436 enrolled pts with
R/R PMBL after autologous hematopoietic cell transplantation (auto
HCT) or 2 prior multiagent chemotherapy regimens if ineligible for
autoHCT. Pts received NIVO (240 mg IV) +BV (1.8 mg/kg IV) every
3 weeks until disease progression or unacceptable toxicity. Primary
endpoints were investigatorassessed ORR per Lugano 2014 criteria
and safety. Secondary endpoints were duration of response (DOR),
CR rate, duration of CR, progressionfree survival (PFS), and overall
survival (OS).
Results: Among 30 pts, median age was 35.5 years. At a median
FU of 33.7 months, ORR was 73% (95% CI, 54–88) and CR rate
was 37%. Median DOR was 31.6 months (95% CI, 23.3–not
estimable [NE]) and median duration of CR was not reached (95%
CI, 27.9–NE) The Kaplan–Meier estimate of median PFS was 26.0
months (95% CI, 2.6–NE; Figure). Among the 17 censored pts in
the PFS analysis, 13 received consolidation therapy, including
FIGURE 1 Progressionfree survival (PFs) and Overall Survival (OS) according to ACVBP, CHOP14 and CHOP21 plus antiCD20
treatment groups
SUPPLEMENT ABSTRACTS
-
93
autoHCT (n =6) or allogeneicHCT (n =6) with or without
radiotherapy (RT), and RT alone (n =1); of pts with assessments
1 year after autoHCT and alloHCT, 5/6 and 5/5 had CR,
respectively. Four pts remained progressionfree in FU for 137+,
273+, 372+, and 606+days after discontinuation of NIVO +BV
(3 due to maximum clinical benefit and 1 due to study drug
toxicity) without receiving subsequent therapy. The OS rate was
79% (95% CI, 59–90) at 12 months and 76% (95% CI, 55–88) at
24 months; median OS was not reached. Anygrade treatment
related adverse events (TRAEs) occurred in 83% of pts, most
frequently neutropenia (30%; all grade 3–4) and peripheral neu-
ropathy (27%; 10% grade 3–4). TRAEs led to discontinuation in 6
pts. No graftversushost disease was reported in the 6 pts
receiving subsequent alloHCT. There were 8 deaths, 5 due to
disease progression and none considered related to study drug
toxicity.
Conclusions: In this extended FU of CheckMate 436, NIVO +BV
demonstrated durable responses and longterm survival benefits;
4 pts remained progressionfree without consolidation after NIVO
+BV. Safety was consistent with prior findings. These results
further support NIVO +BV as a treatment option for pts with R/R
PMBL.
The research was funded by: Bristol Myers Squibb
Keywords: Aggressive Bcell nonHodgkin lymphoma, Combination
Therapies, Immunotherapy
Conflicts of interests pertinent to the abstract
P. L. Zinzani
Consultant or advisory role: Servier, Merck, Janssen, Eusapharma,
Takeda, Incyte, Gilead, Novartis
Honoraria: Servier, Merck, Janssen, Eusapharma, Takeda, Incyte,
Gilead, Novartis
A. Santoro
Consultant or advisory role: Bristol Myers Squibb, Servier, Gilead,
Pfizer, Eisai, Bayer, Merck Sharp & Dohme, Arqule, Sanofi
Other remuneration: Takeda, Bristol Myers Squibb, Roche, AbbVie,
Amgen, Celgene, Servier, Gilead, AstraZeneca, Pfizer, Arqule, Lilly,
Sandoz, Eisai, Novartis, Bayer, Merck Sharp & Dohme
G. Gritti
Consultant or advisory role: Takeda, IQvia, Gilead Sciences
Honoraria: Amgen, Roche
Research funding: Gilead Sciences
Educational grants: Roche, Abbvie, Gilead Sciences, Abbvie
P. Brice
Honoraria: MDS, Takeda
P. M. Barr
Consultant or advisory role: Bristol Myers Squibb, AbbVie, Janssen,
Genentech, TG therapeutics, Gilead, Merck, Morphosys, Bayer,
Seattle Genetics, Beigene, MEI
J. Kuruvilla
Consultant or advisory role: AbbVie, Bristol Myers Squibb, Gilead,
Karyopharm, Merck, Roche, Seattle Genetics
Honoraria: Amgen, Antengene, Astra Zeneca, Bristol Myers Squibb,
Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche,
Seattle Genetics, TG Therapeutics
Research funding: Canadian Cancer Society, Leukemia and Lym-
phoma Society Canada, Princess Margaret Cancer Foundation,
Janssen, Roche, AstraZeneca
Other remuneration: Karyopharm (DSMB)
D. Cunningham
Consultant or advisory role: OVIBIO on Scientific Advisory Board
Research funding: Amgen, Sanofi, Merrimack, AstraZeneca, Celgene,
MedImmune, Bayer, 4SC, Clovis, Eli Lilly, Janssen, Merck
J. Kline
Consultant or advisory role: Merck
Honoraria: Kite/Gilead, MorphoSys, Karyopharm, Verastem, Seagen
Research funding: Merck, iTeos, Verastem
N. A. Johnson
Consultant or advisory role: Merck, Bristol Myers Squibb, Roche,
Seattle Genetics, AbbVie, Jansson, Gilead
Honoraria: Roche
Research funding: AbbVie, Roche
N. MehtaShah
Consultant or advisory role: Kiowa Hakka Kirin, Karyopharm Ther-
apeutics, C4 Therapeutics, Daiichi Sankyo, Ono Pharmaceuticals,
Secura Bio
Research funding: Bristol Myers Squibb, Celgene, Verastem, Innate
Pharmaceuticals, Corvus Pharmaceuticals, Genentech/Roche
M. Fanale
Employment or leadership position: Seattle Genetics
Stock ownership: Seattle Genetics
S. Francis
Employment or leadership position: Bristol Myers Squibb
Stock ownership: Bristol Myers Squibb
Progressionfree survival
94
-
SUPPLEMENT ABSTRACTS
A. J. Moskowitz
Honoraria: Imbrium Therapeutics L.P., Merck, and Seattle Genetics
Research funding: Miragen, Seattle Genetics, Merck, Bristol Myers
Squibb, and Incyte
SESSION 8: PERIPHERAL T/NKCELL LYMPHOMAS
052 |ESA VERSUS MESA WITH SANDWICHED
RADIOTHERAPY IN PATIENTS WITH EARLYSTAGE NATURAL
KILLER/TCELL LYMPHOMA: A MULTICENTRE, RANDOMISED,
PHASE 3, NONINFERIORITY TRIAL
H.J. Zhong
1
, S. Cheng
2
, X. Zhang
3
, B. Xu
4
, J.Y. Chen
5
, X.F. Jiang
6
,
Y. Hu
7
, G.H. Cui
8
, J.Y. Wei
9
, W.B. Qian
10
, X.B. Huang
11
, M. Hou
12
,
F. Yan
13
, X. Wang
14
, Y.P. Song
15
, J.D. Hu
16
, Y.H. Liu
17
, X.J. Ma
18
,
F. Li
19
, C.Y. Wu
20
, J.M. Chen
21
, L. Yu
22
, O. Bai
23
, J.Y. Xu
24
, ZunM.
Zhu
25
, L. Liu
26
, X. Zhou
27
, L. Huang
28
, Y. Tong
29
, T. Niu
30
, D.P. Wu
31
,
J. Xiong
32
, H. Zhang
33
, C.F. Wang
34
, B. Ouyang
35
, H.M. Yi
36
,
G. Cai
37
, B. Li
38
, J. Liu
39
, Z.F. Li
40
, R. Xiao
41
, L.Q. Wang
42
,
Y.J. Jiang
43
, Y.Y. Liu
44
, X.Y. Zheng
45
, P.P. Xu
46
, H.Y. Huang
47
,
L. Wang
48
, S.J. Chen
49
, W.L. Zhao
50
1
Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of
Medicine, Department of Hematology, Shanghai, China,
2
Ruijin Hospital
Affiliated to Shanghai Jiao Tong University School of Medicine,
Department of Hematology, Shanghai, China,
3
Xinqiao Hospital,
Department of Hematology, Chongqing, China,
4
First Affiliated Hospital
of Xiamen University, Department of Hematology, Xiamen, China,
5
Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of
Medicine, Department of Radiation Oncology, Shanghai, China,
6
Ruijin
Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,
Department of Nuclear Medicine, Shanghai, China,
7
Union Hospital,
Tongji Medical College, Huazhong University of Science and Technology,
Institute of Hematology, Wuhan, China,
8
Union Hospital, Tongji Medical
College, Huazhong University of Science and Technology, Institute of
Hematology, Wuhan, China,
9
First Affiliated Hospital of Zhejiang
University School of Medicine, Department of Hematology, Hangzhou,
China,
10
Second Affiliated Hospital of Zhejiang University School of
Medicine, Department of Hematology, Hangzhou, China,
11
Sichuan
Provincial People's Hospital, Department of Hematology, Chengdu,
China,
12
Qilu Hospital, Shandong University, Department of
Hematology, Jinan, China,
13
First People's Hospital of Changzhou,
Department of Hematology, Changzhou, China,
14
Shandong Provincial
Hospital Affiliated to Shandong University, Department of Hematology,
Jinan, China,
15
Affiliated Cancer Hospital of Zhengzhou University,
Department of Hematology, Zhengzhou, China,
16
Fujian Medical
University Union Hospital, Department of Hematology, Fuzhou, China,
17
Jiangsu Cancer Hospital, Department of Medical Oncology, Nanjing,
China,
18
Shanghai Cancer Center, Fudan University, Department of
Medical Oncology, Shanghai, China,
19
First Affiliated Hospital of
Nanchang University, Department of Hematology, Nanchang, China,
20
Second Hospital of Lanzhou University, Department of Hematology,
Lanzhou, China,
21
First Affiliated Hospital of Fujian Medical University,
Department of Hematology and Rheumatology, Fuzhou, China,
22
The
Second Affiliated Hospital of Nanchang University, Department of
Hematology, Nanchang, China,
23
First Hospital of Jilin University,
Department of Hematology, Jilin, China,
24
Nanjing Drum Tower
Hospital, Department of Hematology, Nanjing, China,
25
Henan Province
People's Hospital, Department of Hematology, Zhengzhou, China,
26
Tangdu Hospital, Department of Hematology, Xi'an, China,
27
Wuxi
People's Hospital Affiliated to Nanjing Medical University, Department
of Hematology, Wuxi, China,
28
Hospital (T.C.M) Affiliated to Southwest
Medical University, Department of Oncology and Hematology, Luzhou,
China,
29
Shanghai General Hospital Affiliated to Shanghai Jiao Tong
University, Department of Hematology, Shanghai, China,
30
West China
Hospital, Sichuan University, Department of Hematology, Chengdu,
China,
31
First Affiliated Hospital of Soochow University, Institute of
Hematology, Suzhou, China,
32
Ruijin Hospital Affiliated to Shanghai
Jiao Tong University School of Medicine, Department of Hematology,
Shanghai, China,
33
Ruijin Hospital Affiliated to Shanghai Jiao Tong
University School of Medicine, Department of Otolaryngology, Shanghai,
China,
34
Ruijin Hospital Affiliated to Shanghai Jiao Tong University
School of Medicine, Department of Pathology, Shanghai, China,
35
Ruijin
Hospital Affiliated to Shanghai Jiao Tong University School of Medicine,
Department of Pathology, Shanghai, China,
36
Ruijin Hospital Affiliated
to Shanghai Jiao Tong University School of Medicine, Department of
Pathology, Shanghai, China,
37
Ruijin Hospital Affiliated to Shanghai
Jiao Tong University School of Medicine, Department of Radiation
Oncology, Shanghai, China,
38
Ruijin Hospital Affiliated to Shanghai Jiao
Tong University School of Medicine, Department of Nuclear Medicine,
Shanghai, China,
39
Xinqiao Hospital, Department of Hematology,
Chongqing, China,
40
First Affiliated Hospital of Xiamen University,
Department of Hematology, Xiamen, China,
41
Sichuan Provincial
People's Hospital, Department of Hematology, Chengdu, China,
42
Qilu
Hospital, Shandong University, Department of Hematology, Jinan,
China,
43
Shandong Provincial Hospital Affiliated to Shandong
University, Department of Hematology, Jinan, China,
44
Affiliated Cancer
Hospital of Zhengzhou University, Department of Hematology,
Zhengzhou, China,
45
Fujian Medical University Union Hospital,
Department of Hematology, Fuzhou, China,
46
Ruijin Hospital Affiliated
to Shanghai Jiao Tong University School of Medicine, Department of
Hematology, Shanghai, China,
47
Shanghai Jiao Tong University School
of Medicine, School of Public Health, Shanghai, China,
48
Ruijin Hospital
Affiliated to Shanghai Jiao Tong University School of Medicine,
Department of Hematology, Shanghai, China,
49
Shanghai Institute of
Hematology, State Key Laboratory of Medical Genomics, National
Research Center for Translational Medicine at Shanghai, Ruijin Hospital
Affiliated to Shanghai Jiao Tong University School of Medicine,
Department of Hematology, Shanghai, China,
50
Shanghai Institute of
Hematology, State Key Laboratory of Medical Genomics, National
Research Center for Translational Medicine at Shanghai, Ruijin Hospital
Affiliated to Shanghai Jiao Tong University School of Medicine,
Department of Hematology, Shanghai, China
SUPPLEMENT ABSTRACTS
-
95
Background: Natural killer/Tcell lymphoma (NKTL) is a highly
aggressive lymphoma that usually treated with intensive chemo-
therapy. Our phase 2 study showed that methotrexate, etoposide,
dexamethasone, pegaspargase (MESA) regimen with sandwiched
radiotherapy was safe and effective for earlystage NKTL. However,
it is unclear whether intensity of chemotherapy can be further
reduced for earlystage NKTL in the era of asparaginase with sand-
wiched radiotherapy.
Methods: We conducted a multicentre, randomised, phase 3 non
inferiority trial involving patients aged 1470 years with newly
diagnosed earlystage NKTL from 27 centres of the Multicenter
HematologyOncology Programs Evaluation System in China. Ran-
domisation was computerassisted with a block size of four. In-
vestigators and patients were not masked to treatment
assignment. Patients were randomly assigned in a 1:1 ratio to
receive four cycles of lowintensity ESA (pegaspargase, oral eto-
poside and dexamethasone) with sandwiched radiotherapy or four
cycles of MESA with sandwiched radiotherapy. The primary end
point was overall response rate. A noninferiority margin of 10.0%
was designed for ESA with sandwiched radiotherapy versus MESA
with sandwiched radiotherapy. The primary and safety analysis
were performed in the modified intentiontotreat population
including patients who received at least one cycle of assigned
treatment. The trial was prospectively registered at ClinicalTrials.
gov, NCT02631239.
Findings: Between March 16, 2016, and July 17, 2020, a total of 256
patients were enrolled, and 248 (125 of ESA with sandwiched
radiotherapy and 123 of MESA with sandwiched radiotherapy) made
up the modified intentiontotreat population. The overall response
rate was 88.8% (95% confidence interval [CI] 83.294.4) in the ESA
with sandwiched radiotherapy group and 86.2% (80.092.4) in the
MESA with sandwiched radiotherapy group, with an absolutely rate
difference of 2.6 percentage points (3.68.8). The lower limit of the
95%CI for the absolute rate difference is within the designated non
96
-
SUPPLEMENT ABSTRACTS
inferiority margin. Perprotocol analysis and sensitivity analysis
supported this result. Adverse events of grade 3 or higher occurred
in 42 (33.6%) of the patients with ESA with sandwiched radiotherapy
and 81 (65.9%) with MESA with sandwiched radiotherapy. Three
patients in the ESA with sandwiched radiotherapy group died due to
adverse events. Five patients in the MESA with sandwiched radio-
therapy group died due to adverse events.
Interpretation: Lowintensity ESA with sandwiched radiotherapy is
highly effective and nonintravenous treatment, with low toxicity and
outpatient basis, and can be considered as firstline treatment option
in newly diagnosed earlystage NKTL.
Keywords: Combination Therapies
No conflicts of interests pertinent to the abstract.
053 |ALLOGENEIC HEMATOPOIETIC CELL
TRANSPLANTATION FOR PERIPHERAL TCELL LYMPHOMA:
COMPARABLE OUTCOMES OF HAPLOIDENTICAL VS. MATCHED
DONORS. A CIBMTR & EBMT ANALYSIS
P. Dreger
1
, M. Ngoya
1
, C. Litovich
2
, H. Finel
1
, A. F Herrera
2
,
C. Sauter
2
, M. KharfanDabaja
2
, A. Sureda
1
, D. Blaise
1
, L. Castagna
1
,
P. Corradini
1
, R. Pastano
1
, M. Arat
1
, A. Boumendil
1
, S. Dietrich
1
,
N. Schmitz
1
, B. Glass
1
, S. Montoto
1
, M. Hamadani
2
1
EBMT, Lymphoma Working Party, Paris, France,
2
CIBMTR, Lymphoma
Working Committee, Milwaukee, Wisconsin, USA
Introduction: The advent of immunosuppression with post
transplant cyclophosphamide (ptCY) has facilitated allogeneic he-
matopoietic cell transplantation (alloHCT) from haploidentical do-
nors in patients lacking a matched donor. The aim of this study was to
compare the outcomes of ptCY haploidentical transplantation
(haploHCT) with that of alloHCT from matched sibling donors
(msdHCT), matched unrelated donors with invivo Tcell depletion
(mudHCTTCD), and matched unrelated donors without Tcell
depletion (mudHCTTRD) in patients with peripheral Tcell lym-
phoma (PTCL).
Methods: Eligible for this retrospective registry study were patients
aged 18 or older who had undergone alloHCT for anaplastic large cell
lymphoma(ALCL), angioimmunoblastic Tcell lymphoma (AITL), or
PTCLnot other specified (PTCLNOS) from the 4 donor types
described between 2008 and 2018 and were registered with the
CIBMTR or the EBMT. Coprimary endpoints were overall survival
(OS) and progressionfree survival (PFS); secondary endpoints
included engraftment, acute and chronic GVHD, nonrelapse mor-
tality (NRM), and relapse/progression incidence (RI).
Results: Altogether 1942 patients were eligible (haploHCT 237;
msdHCT 911; mudHCTTCD 468; mudHCTTRD 326). HaploHCT
and matched aloHCT recipients were comparable for histology, age,
gender, comorbidity score, pretreatment lines, prior autoHCT, and
disease status at HCT. However, haploHCT patients were more likely
to have a Karnofsky score of 90100, and had more often received
reduced intensity conditioning as well as bone marrow grafts
(31% vs 6%).
On univariate and multivariate comparisons, OS and PFS, RI, and
NRM were not significantly different between haploHCT, msdHCT,
mudHCTTCD, and mudHCTTRD with 3year estimates for OS and
PFS of 60%, 63%, 59%, and 64; and 50%, 50%, 48%, and 52%,
respectively. Engraftment was significantly delayed after haploHCT
(neutrophils >0.5/nl at d +28 86% vs 95%, 94%, 97%, respectively, p
<0.001; platelets >20/nl at d +100 80% vs 96%, 93%, 96%,
respectively, p <0.001). Whilst risk of acute GVHD was comparable
between haploHCT, msdHCT, and mudHCTTCD, there was a lower
1year cumulative incidence of chronic GVHD after haploHCT (28%
vs 41%, 35%, and54%; p <0.001); retaining significance after
multivariate adjustment for confounders. Factors significantly
impairing both OS and PFS on multivariate analysis were advanced
disease status at alloHCT, age >50, and poor Karnofsky score. Pa-
tients undergoing alloHCT in 1
st
line had significantly better OS than
patients allografted later.
Conclusions: These data, the largest study to date, confirm that
alloHCT can result in durable PFS in a sizable proportion of patients
with ALCL, AITL, and PTCLNOS. The outcome of haploHCT in PTCL
is comparable to that of matched donor alloHCT, suggesting that
haploHCT might be a valid alternative in this setting.
Keywords: Stem Cell Transplant
Conflicts of interests pertinent to the abstract
P. Dreger
Consultant or advisory role: Gilead, Novartis, BMS, Bluebird Bio,
Takeda
054 |LACUTAMAB IN PATIENTS (PTS) WITH ADVANCED
MYCOSIS FUNGOIDES (MF) ACCORDING TO KIR3DL2
EXPRESSION: EARLY RESULTS FROM THE TELLOMAK PHASE 2
TRIAL
M. Bagot
1
, Y. Kim
2
, P. L. Zinzani
3
, S. Dalle
4
, M. Beylotbarry
5
,
P. L OrtizRomero
6
, A. Cambalia
7
, O. Dereure
8
, L. Mortier
9
,
E. Jacobsen
10
, F. Rotolo
11
, H. A Azim Jr
12
, P. Porcu
13
1
Hopital St Louis, Dermatology, Paris, France,
2
Stanford Cancer Center,
Dermatology, San Francisco, USA,
3
Policlinico S. OrsolaMalpighi,
Oncology Hematology, Bologna, Italy,
4
Hospices Civils de Lyon,
Dermatology, Lyon, France,
5
Centre Hospitalier Universitaire de
Bordeaux Hôpital SaintAndre, Dermatology, Bordeaux, France,
6
Hospital 12 de Octubre Medical School, Dermatology, Madrid, Spain,
7
Hospital Clínic de Barcelona, Dermatology, Barcelona, Spain,
8
CHU
Montpellier, Dermatology, Montpellier, France,
9
CHRU de Lille Hôpital
Claude Huriez, Dermatology, Lille, France,
10
DanaFarber Cancer
Institute, Oncology Hematology, Boston, USA,
11
Innate Pharma, Clinical
Affaires, Marseille, France,
12
Innate Pharma, Clinical Development,
Marseille, France,
13
Thomas Jefferson University, Hematology Oncology,
Philadelphia, USA
SUPPLEMENT ABSTRACTS
-
97
Background: KIR3DL2 is a killer immunoglobulinlike receptor,
expressed in >90% of Sézary Syndrome (SS) pts and 50% in pts with
MF. Lacutamab is a humanized firstinclass monoclonal antibody
designed to deplete KIR3DL2expressing cells via antibody
dependent cellcytotoxicity and phagocytosis. In a previous phase 1
trial, lacutamab showed adequate safety profile with no dose limiting
toxicities and a global response rate of 42.9% in pts with SS, with a
median time to response of 4.9 months (m).
Methods: TELLOMAK is an openlabel, multicohort, international
phase II trial. Up to 148 pts are planned to be enrolled. Pts are
allocated to one of three cohorts: Cohort 1: SS, Cohort 2: KIR3DL2
expressing (1%) MF and Cohort 3: KIR3DL2 nonexpressing MF,
based on central KIR3DL2 testing. Eligible pts should have received
at least 2 prior systemic therapies with no evidence of large cell
transformation. Lacutamab 750 mg is administered as an intravenous
(i.v.) infusion weekly x 5 weeks (w), every 2 w x 10 then every 4 w,
until progression or unacceptable toxicity. The primary endpoint is
global confirmed response, evaluated using the International
Consensus Criteria. Secondary endpoints include safety, quality of
life, other efficacy endpoints, and biomarker analysis. Evaluable pts
should have at least one response assessment 5 w after treatment
initiation. In each of the MF cohorts, the study follows a Simon 2
stage design in which 21 and 18 pts were required in stage 1 for
Cohorts 2 and 3, respectively with early termination if <3 global
confirmed responses per cohort were observed. Here we report early
stage 1 data for the two MF cohorts.
Results: As of January 20 2021, recruitment in stage 1 for both
cohorts 2 and 3 is ongoing, with 12 pts enrolled in each
cohort. Median age for all 24 pts is 57 years (range: 1981). At
study entry, 42% (n =5) and 17% (n =2) had stage III/IV in
cohorts 2 and 3, respectively. Median number of prior systemic
therapies is 3.5 (range: 210). At a median followup of 2.8 m
(range: 0.314.1 m), 7 and 6 pts in cohort 2 and 3, respectively,
are ongoing treatment. Overall, 19 pts were evaluable for
response in Cohort 2 (n =11) and Cohort 3 (n =8). In Cohort 2,
5 skin responses were observed, of whom 3 had global confirmed
responses (1 complete response, 2 partial responses). 7 pts had
global stable disease. No responses are reported yet in Cohort 3.
Adverse events (AEs) of any grade were observed in 17/24 pts
(71%), of which 10/24 (42%) were treatmentrelated [TR]. Grade
3 AEs were observed in 2/24 (8%) pts, of which 1/24 (4%) was
TR. Most common AEs were asthenia (N =6, 25%; TR: 2),
pruritus (N =3, 12%; TR: 0), and peripheral oedema (N =2, 8%;
TR: 1).
Conclusion: Lacutamab met the predefined threshold of activity in
the KIR3DL2 expressing MF cohort required to expand recruitment
to 50 pts. Safety profile is reassuring and consistent with previous
phase 1 data. Updated results on all stage 1 pts from cohort 2 and 3
will be presented.
The research was funded by: Innate Pharma
Keywords: Cutaneous nonHodgkin lymphoma, Molecular Targeted
Therapies
Conflicts of interests pertinent to the abstract
M. Bagot
Consultant or advisory role: Innate Pharma, Kyowa Kirin, Takeda,
Galderma, Helsinn, recordati rare diseases
P. L OrtizRomero
Consultant or advisory role: Kyowa Kirin, Takeda, 4SC, Helsinn,
Miragen, Innate Pharma, Recordati Rare diseases
F. Rotolo
Employment or leadership position: Innate Pharma
Stock ownership: Innate Pharma
H. A. Azim Jr
Employment or leadership position: Innate Pharma
Stock ownership: Innate Pharma
P. Porcu
Consultant or advisory role: Daiichi
Honoraria: Viracta, Innate Pharma, Kyowa Kirin, Verastem, Daiichi
Research funding: Viracta, Innate Pharma, Kyowa Kirin, Daiichi,
BeiGene, Incyte
Other remuneration: Scientific Boards: Viracta, Innate Pharma,
Kyowa Kirin, BeiGene
055 |MULTICENTER PHASE II STUDY OF ROMIDEPSIN PLUS
LENALIDOMIDE FOR PATIENTS WITH PREVIOUSLY UNTREATED
PERIPHERAL TCELL LYMPHOMA (PTCL)
J. Ruan
1
, J. M Zain
2
, B. Palmer
3
, B. Borko Jovanovic
4
, X. Mi
4
,
A. Swaroop
5
, J. Winter
3
, L. I Gordon
3
, R. Karmali
3
, B. Pro
3
1
Weill Cornell Medicine, New York Presbyterian Hospital, Medicine,
HematologyOncology, New York City, New York, USA ,
2
City of Hope
Comprehensive Cancer Center, Medicine, Duarte, USA,
3
Robert H. Lurie
Comprehensive Cancer Center, Northwestern University Feinberg School
of Medicine, Medicine, Chicago, USA,
4
Northwestern University Fein-
berg School of Medicine, Department of Preventive Medicine, Chicago,
USA,
5
Northwestern University Feinberg School of Medicine, Depart-
ment of Medicine, Chicago, USA
Introduction: PTCL are aggressive malignancies associated with poor
prognosis when treated with cytotoxic chemotherapy. Novel agents,
such as HDAC inhibitor romidepsin and immunomodulatory agent
lenalidomide, have shown clinical activities both as single agents and
when combined in R/R PTCL. We hypothesize that upfront treatment
with these agents is an effective and welltolerated option to defer
chemotherapy, particularly in patients who are not candidates for
intensive approach. We report the findings of the first chemofree
combination of romidepsin plus lenalidomide as initial treatment
for PTCL (ClinicalTrials.govNCT02232516).
Methods: Patients with previously untreated PTCL who were over
60 or noncandidates for chemotherapy based on comorbidity CIRS
score were eligible. Treatment was initiated with romidepsin 10
mg/m2 IV on d 1, 8, 15, and lenalidomide 25 mg PO on d 121 of
98
-
SUPPLEMENT ABSTRACTS
28day cycle for up to 1 year, unless discontinued prior due to
POD, toxicities, or withdrawal of consent. The primary objective
was to evaluate ORR per Cheson criteria. Secondary objectives
included safety, PFS, OS, DOR, and delay to chemotherapy. The
sample size was 20 evaluable patients, which allows to estimate
the underlying true response rate with the margin of error of an
approximate 95% confidence interval equal to 0.22, assuming the
true ORR =0.5.
Results: The study enrolled 29 subjects at 3 US centers, including
16 (55%) AITL, 11 (38%) PTCLNOS, 1 ATLL and 1 EATCL. The
median age was 75 (range 4984), and M:F ratio was 1:1. Nineteen
(66%) had stage III/IV disease, 23 (79%) had elevated LDH, and 9
(31%) had IPI 35. Treatment was generally well tolerated
with expected side effects. Grade 34 hematologic toxicities
included neutropenia (45%), thrombocytopenia (34%) and anemia
(28%). Grade 34 nonhematologic toxicities included hyponatremia
(45%), hypertension (38%), hypoalbuminemia (24%), fatigue (17%),
hyperglycemia (14%), hypokalemia (14%), dehydration (10%), lung
infection (10%) and sepsis (10%). At a median followup of 8
months, 20 subjects were evaluable and received a median treat-
ment of 6 cycles. The ORR was 75% (95%CI: 50.9%, 91.3%) with
CR at 30% (11.9%, 54.3%). For AITL, the ORR was 84.6% (54.6%,
98.1%) with CR at 38.5% (13.9%, 68.4%). Median DOR was 4.2
months for all responders, and 14.3 months for CR patients.
The estimated 1yr PFS was 54.3% with 3yr PFS at 36.2%, and
the estimated 1yr OS was 76.0% with 3yr OS at 51.3%. Two
subjects moved onto consolidative ASCT in remission, and 4
received additional cytotoxic chemotherapy after progression.
Conclusions: This study provides the first demonstration
that chemofree biologic combination of romidepsin and lenalido-
mide is feasible and effective as initial therapy for PTCL patients
who are not candidates for cytotoxic chemotherapy. These data
justify further evaluation of such novel agents as a frontline
strategy.
EA previously submitted to ASCO 2021
The research was funded by: BMS / Celgene
Keywords: Molecular Targeted Therapies, Targeting the Tumor
Microenvironment
Conflicts of interests pertinent to the abstract
J. Ruan
Consultant or advisory role: BMS/Celgene, Seagen, Daiichi Sankyo
Honoraria: Kite Pharma
Research funding: BMS/Celgene, AstraZeneca, Pharmacyclics, Sea-
gen, Daiichi Sankyo
J. M. Zain
Consultant or advisory role: Verastem, Legend Biotech, Ono
Pharmaceutical
Honoraria: Seagen, Verastem, Kyowa Kirin
Research funding: Seagen, Crispr Therapeutics, Affimed Therapeu-
tics, Onco Taris
J. Winter
Consultant or advisory role: Merck
Honoraria: Merck, Karyopharm Therapeutics
B. Pro
Consultant or advisory role: Corvus Pharmaceuticals
Honoraria: Takeda, Seagen, Portola Pharmaceuticals, Celgene, Bayer,
Kyowa Kirin
Research funding: Celgene, Takeda, Verastem
SUPPLEMENT ABSTRACTS
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99
056 |THE COMBINATION OF DUVELISIB AND ROMIDEPSIN
(DR) IS HIGHLY ACTIVE AGAINST RELAPSED/REFRACTORY
PERIPHERAL TCELL LYMPHOMA WITH LOW RATES OF
TRANSAMINITIS: FINAL RESULTS
S. M. Horwitz
1
, A. J. Moskowitz
1
, N. MehtaShah
2
, E. D. Jacobsen
3
,
M. S. Khodadoust
4
, N. Ganesan
1
, E. Drill
5
, H. Hancock
1
, T. Davey
1
,
P. Myskowski
6
, C. Maccaro
1
, W. Blouin
1
, J. Schwieterman
2
,
E. Cathcart
1
, S. Fang
7
, L. Perez
1
, S. Ryu
1
, N. Galasso
1
, D. Straus
1
,
D. C. Fisher
3
, A. Kumar
1
, A. Noy
1
, L. Falchi
1
, A. Dogan
8
, Y. H. Kim
7
,
D. Weinstock
3
1
Memorial Sloan Kettering Cancer Center, Medicine/Lymphoma, New
York, New York, USA,
2
Washington University, Medicine, Olivette, USA,
3
Dana Farber Cancer Institute, Medical Oncology/Hematologic Neoplasia,
Boston, USA,
4
Stanford University Medical Center, Medicine (Oncology)
and Dermatology, Stanford, USA,
5
Memorial Sloan Kettering Cancer
Center, EpidemiologyBiostatistics, New York, USA,
6
Memorial Sloan
Kettering Cancer Center, Medicine/Dermatology, New York, USA,
7
Stan-
ford University School of Medicine and Stanford Cancer Institute, Medi-
cine (Oncology) and Dermatology, Stanford, USA,
8
Memorial Sloan
Kettering Cancer Center, Pathology, New York, USA
Introduction: Standard therapies for most relapsed/refractory (R/R)
Tcell lymphomas (TCL) have overall response rates (ORR) of 25%
35%. Phosphoinositide3kinase (PI3K) δand γisoforms can promote
tumor cell autonomous and nonautonomous effects in TCL. Initial
studies of the PI3K‐δ/γinhibitor duvelisib (D) in R/R TCL showed an
ORR of 50% and CR of 19%, but also a 40% rate of grade (Gr) 3/4
ALT elevation at the MTD of 75 mg BID (Horwitz et al Blood 2018).
Based on preclinical data, we initiated a phase I study of D with either
romidepsin (R) or bortezomib. Based on efficacy and safety, Arm A
(DR) was expanded to further describe safety and subtypespecific
efficacy.
Methods: 66 patients were treated on Arm A, with 59 at the MTD of
D 75mg BID +R 10 mg/m2 on days 1, 8, 15 of a 28 day cycle with
prophylaxis against VZV and PJP. Response was assessed q2 cycles x
3 then q3 cycles. 10 patients received 1 cycle (Lead In) of D 75 mg
BID alone prior to combination DR. Patients proceeding to transplant
were censored.
Results: 55 patients with PTCL and 11 with CTCL were treated
(Table 1). No DLTs were seen in the phase 1 on Arm A so dose level 3
(D 75 +R 10) was deemed the MTD.
At the MTD, 50/59 (85%) had AEs Gr 34 (no Gr 5) possibly related
to study drug. AEs Gr 3 in 10% of pt were: neutropenia (36%),
diarrhea (15%), increased ALT/AST (14%), thrombocytopenia (10%),
and infection (10%). 5 patients (9%) had Gr 3 rash. 12 had any Gr
oropharyngeal/esophageal candidiasis; 2 Gr3. In 10 patients who
began on Donly Lead In, 4 (40%) had Gr 3 ALT/AST and 3/10 had
Gr 3 diarrhea. By contrast, only 4 /49 (8%) who got R +D in cycle 1
had Gr 34 ALT/AST (p =.022) and 6/49 had Gr 3 diarrhea (p =
.170).
64/66 patients were evaluable for response. ORR was 55% (35/64)
and CR was 34% (22/64). In PTCL, ORR was 58% (31/53) and CR
was 42% (22/53). In CTCL, ORR was 36% (4/11), all PR. Response
by histology is in Table 1. Of responders, 15/35 (43%) proceeded
to alloSCT with curative intent, after a median of 4 cycles. Me-
dian PFS was 6.9 m (PTCL) and 5.5 m (CTCL) and median DOR
was 8.1 m. 4 subjects had CR to single agent D on Leadin and did
not proceed to DR; 2/4 went to SCT and 1/4 remains on D at
42m.
Conclusion: DR is highly active in R/R PTCL. Adding Romidepsin to
Duvelisib 75 mg BID is safe and reduces Gr 34 transaminitis
compared to Duvelisib at the same dose. The high rates of CR and
frequent bridging to allotransplant support the value of DR for pa-
tients with R/R PTCL.
The research was funded by Verastem/SecuraBio for this
clinical trial
Keywords: Aggressive Tcell nonHodgkin lymphoma, Chemotherapy,
Combination Therapies
TABLE 1Response by Histology
100
-
SUPPLEMENT ABSTRACTS
Conflicts of interests pertinent to the abstract
S. M. Horwitz
Consultant or advisory role: Acrotech Biopharma, ADC Therapeutics,
Astex, C4 Therapeutics, Celgene, Janssen, Kura Oncology, Kyowa
Hakko Kirin, Myeloid Therapeutics, ONO Pharmaceuticals, Seattle
Genetics, Shoreline Bio, Takeda, Trillium Therapeutics, Tubulis,
Verastem, SecuraBio, and Vividion Therapeutics.
Honoraria: Takeda
Research funding: ADC Therapeutics, Affimed, Aileron, Celgene,
Daiichi Sankyo, Forty Seven, Inc., Kyowa Hakko Kirin, Millennium/
Takeda, Seattle Genetics, Trillium Therapeutics, and Verastem/
SecuraBio
A. J. Moskowitz
Consultant or advisory role: Imbrium Therapeutics L.P, Janpix Ltd.,
Merck, Seattle Genetics, and Takeda
Research funding: ADC Therapeutics, Miragen, Seattle Genetics,
Merck, BristolMyers Squibb, and Incyte
N. MehtaShah
Consultant or advisory role: Kiowa Hakka Kirin, Karyopharm Ther-
apeutics, C4 Therapeutics, Daiichi Sankyo, Ono Pharmaceuticals,
SecuraBio
Research funding: Bristol Myers Squibb, Celgene, Verastem, Innate
Pharmaceuticals, Corvus Pharmaceuticals, Genentech/Roche
D. C. Fisher
Consultant or advisory role: Verastem
A. Kumar
Consultant or advisory role: Celgene, Kite Pharmaceuticals
Research funding: Abbvie Pharmaceuticals, Adaptive Bio-
technologies, Pharmacyclics, Seattle Genetics, Astra Zeneca
Steering Committee for MCL Registry
A. Dogan
Consultant or advisory role: Corvus Pharmaceuticals, Physicians’
Education Resource, Seattle Genetics, Takeda, Roche, EUSAPharma,
PeerView
Research funding: Roche and Takeda
D. Weinstock
Consultant or advisory role: Secura Pharma
Research funding: Verastem
057 |EARLY SAFETY AND EFFICACY DATA FROM A PHASE I/II
TRIAL OF DZD4205, A SELECTIVE JAK1 INHIBITOR, IN
RELAPSED/REFRACTORY PERIPHERAL TCELL LYMPHOMA
W.S. Kim
1
, D.H. Yoon
2
, Y. Song
3
, Y. Koh
4
, J. Cao
5
, D. Ji
5
, H. Yang
6
,
H.S. Eom
7
, H. Jing
8
, J.Y. Kwak
9
, W.S. Lee
10
, J.S. Lee
11
, H.J. Shin
12
,
J. Jin
13
, M. Wang
14
, J. Li
15
, X. Huang
15
, X. Deng
16
, Z. Yang
15
, J. Zhu
3
1
Samsung Medical Center, Department of Hematology and Oncology,
Seoul, Korea,
2
Asan Medical Center, Department of Oncology
Hematologic Cancer & BMT center, Seoul, Korea,
3
Peking University
Cancer Hospital, Department of Lymphoma, Beijing, China,
4
Seoul
National University Hospital, Department of HematoOncology Cen-
ter, Seoul, Korea,
5
Fudan University Shanghai Cancer Center, Depart-
ment of Oncology, Shanghai, China,
6
Zhejiang Cancer Hospital,
Department of Lymphoma, Hangzhou, China,
7
National Cancer Center,
Center for Hematologic Malignancy, Goyang, Korea,
8
Peking University
Third Hospital, Department of Hematology, Beijing, China,
9
Chonbuk
National University Hospital, Department of Hematooncology, Jeonju,
Korea,
10
Inje University Busan Paik Hospital, Department of Hemato
oncology, Busan, Korea,
11
Seoul National University Bundang Hospital,
Department of Hematology & Medical Oncology, Seongnam, Korea,
12
Pusan National University Hospital, Department of Hematooncology,
Busan, Korea,
13
The First Affiliated Hospital of Zhejiang University,
Department of Hematology, Hangzhou, China,
14
Dizal Pharmaceuticals,
Bioscience, Shanghai, China,
15
Dizal Pharmaceuticals, Clinical Devel-
opment, Shanghai, China,
16
Dizal Pharmaceuticals, Biostatistics,
Shanghai, China
Introduction: Relapsed or refractory (r/r) peripheral T cell lymphoma
(PTCL) is an aggressive lymphoma with poor prognosis. Most
approved therapies demonstrated overall response rates (ORR) <
30% and short progression free survival. DZD4205 (AZD4205), a
potent and highly selective JAK1 inhibitor, demonstrated profound
antitumor activity in T lymphoma cells in vitro and tumor xenograft
in vivo, suggesting its potential as a therapeutic option for this unmet
medical need. In this abstract, we reported the preliminary data from
the ongoing phase I/II study of DZD4205 treating patients with r/r
PTCL (NCT04105010, JACKPOT8).
Methods: The JACKPOT8 study is an open label single arm study,
which aims to assess the safety, tolerability and antitumor efficacy
of DZD4205 in r/r PTCL. This study includes two parts. In Part A,
subjects with r/r PTCL who relapsed from or were refractory/
intolerant to systemic therapy were enrolled and dosed with
DZD4205 at 150 mg or 250 mg once daily. In Part B, subjects
received DZD4205 at a defined dose. Safety and efficacy were
assessed according to CTCAE version 5.0 and 2014 Lugano clas-
sification, respectively.
Results: As of December 7, 2020, a total of 47 subjects with r/r
PTCL were dosed with DZD4205 (150 mg, n =31; 250 mg, n =
16). Median age was 62.0 years (range: 29 79), and median prior
systemic therapies were 2 lines (range: 1 8). Six subjects had
undergone prior hematopoietic stem cell transplantation. Sixteen
subjects had bone marrow involvement at the baseline. Histologi-
cal subtypes included PTCL not otherwise specified (42.6%),
angioimmunoblastic T cell lymphoma (42.6%), ALK negative
anaplastic large cell lymphoma (6.4%), extranodal nasal NK/T cell
lymphoma (6.4%) and monomorphic epitheliotropic intestinal T cell
lymphoma (2.1%).
Preliminary data showed that 41 subjects (87.2%) experienced
treatment emergent adverse events (TEAEs), among whom 24
(51.1%) had grade 3 TEAEs. According to investigators, 16 subjects
SUPPLEMENT ABSTRACTS
-
101
(34.0%) had grade 3 TEAEs possibly related to DZD4205. The most
common (>10%) grade 3 TEAEs included thrombocytopenia
(23.4%), neutropenia (17.0%), and pneumonia (12.8%). Most TEAEs
were manageable and reversible with or without dose modifications.
As of December 7, 2020, 42 subjects (150 mg, n =27; 250 mg, n =
15) completed at least one posttreatment tumor assessment. At 150
mg, 14 subjects showed tumor response, with ORR of 51.9%, among
whom 6 (22.2%) had complete response. At 250 mg, 6 subjects
showed tumor response, with ORR of 40.0%. Tumor response was
observed in various subtypes. The median duration of response (DoR)
was not reached, and the longest DoR was >12 months. Patient
enrolment is ongoing.
Conclusion: Early results from this ongoing phase I/II study suggest
good tolerability and promising antitumor efficacy of DZD4205 in r/
r PTCL, indicating its potential as a therapeutic option for this unmet
medical need.
The research was funded by: The research was funded by Dizal
(Jiangsu) Pharmaceutical Co., Ltd.
Ongoing Trial
Keywords: Molecular Targeted Therapies, Aggressive Tcell non
Hodgkin lymphoma, Molecular Targeted Therapies
No conflicts of interests pertinent to the abstract.
SESSION 9: MANTLE CELL LYMPHOMA
058 |A SIMPLE EPIGENETIC SIGNATURE DEFINES
TWO BIOLOGIC GROUPS OF MANTLE CELL LYMPHOMA
M. M. Bühler
1
, M. Kulis
1
, M. DuranFerrer
1
, G. Clot
1
, F. Nadeu
1
, A.
Navarro
1
, C. López
1
, E. Giné
1
, S. Beà
1
, E. Campo
1
, J. I. MartínSubero
1
1
Hospital Clínic Barcelona, IDIBAPS, Barcelona, Spain
Background: Mantle cell lymphoma (MCL) is a mature B cell
lymphoma with a generally poor prognosis. However, in the past
decade a subset of MCL with more indolent clinical course and
predominant leukemic disease, termed leukemic nonnodal MCL
(nnMCL), has been identified. In order to tailor treatment taking
into account the different natural course of these diseases, it is
important to confidently diagnose the two MCL subtypes. Current
strategies in the differential diagnosis between nnMCL and con-
ventional MCL (cMCL) include SOX11 expression and a gene
expression signature (LMCL16), but both methods present limi-
tations which pose difficulties in clinical practice. The epigenetic
characterization of MCL (Queirós AC et al., Cancer Cell 2016 and
Nadeu F et al., Blood 2020) identified two disease subtypes (C1
and C2), which mostly represent cMCL and nnMCL respectively.
Furthermore, a SOX11 distal enhancer region was discovered,
which is de novo demethylated in SOX11 positive MCL. Our study
aims to translate the epigenetic subtypes of MCL into a simple
assay, which can be easily implemented in clinical practice and
universally applied to all types of clinical samples. Furthermore we
will analyze the impact of the epigenetic disease subtype on clin-
ical outcome and we will characterize the methylation profile of
regulatory regions of SOX11.
Methods: We identified a 3 CpG signature (DuranFerrer M et al.,
Nature Cancer 2020) that accurately subclassifies MCL into C1
(cMCL) and C2 (nnMCL) MCL. To overcome limitations of previous
methodologies, we designed pyrosequencing assays that can be
applied to any type of clinical sample, including frozen and
formalinfixed paraffinembedded (FFPE) tissues, as well as pe-
ripheral blood samples. Extracted DNA was bisulfite converted,
amplified by PCR and pyrosequenced for quantitative methylation
analysis.
Results: Benchmarking experiments show an excellent technical
reproducibility and high correlation between different sample types
of the same patient. The exploratory study with 71 samples shows a
102
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SUPPLEMENT ABSTRACTS
clear separation in two groups, which correspond to C1 and C2 MCL
(Figure). C1 MCL show SOX11 positivity by immunohistochemistry,
except for one single cases of pleomorphic MCL. All SOX11
expressing MCL show a consistent demethylation in the SOX11
regulatory regions, whereas a majority of SOX11 negative cases have
high methylation levels.
Conclusion: Our study highlights the stability and applicability of a
methylation signature to classify MCL subtypes. Analysis of the
methylation signature in an extended series of cases is currently
ongoing and will allow us to determine the prognostic significance of
the epigenetic subtype of MCL. This epigenetic signature applicable
to any type of clinical samples may represent a novel and accurate
tool for the differential diagnosis of cMCL and nnMCL in clinical
routine.
EA previously submitted to EHA 2021.
The research was funded by: the Ministerio de Ciencia e Innovación
(MCI), grant RTI2018094274BI00 and the NIH, grant
P01CA229100 (to E.C.). M.B. is supported by the Swiss Cancer
League (BIL KLS5130082020) and the NuovoSoldati Foundation
for Cancer Research.
Keywords: Genomics, Epigenomics, and Other Omics, Aggressive B
cell nonHodgkin lymphoma, Pathology and Classification of
Lymphomas
No conflicts of interests pertinent to the abstract.
059 |A COMPLETELY GENETIC PROGNOSTIC MODEL
OVERCOMES CLINICAL PROGNOSTICATORS IN MANTLE CELL
LYMPHOMA: RESULTS FROM THE MCL0208 TRIAL FROM THE
FONDAZIONE ITALIANA LINFOMI (FIL)
S. Ferrero
1
, R. Moia
2
, L. Cascione
3
, G. M. Zaccaria
4
, A. Rinaldi
5
,
B. Alessandria
6
, D. Grimaldi
6
, C. Favini
2
, A. Evangelista
7
, M. Schipani
2
,
F. Narni
8
, C. Stelitano
9
, P. M. Stefani
10
, F. Benedetti
11
, M. Mian
12
,
I. Casaroli
13
, M. Zanni
14
, C. Castellino
15
, V. Pavone
16
, S. Galimberti
17
,
F. Re
18
, D. Rossi
19
, S. Cortelazzo
20
, G. Gaidano
2
, M. Ladetto
21
,
F. Bertoni
19
1
Hematology, Department of Molecular Biotechnologies and Health
Sciences, University of Torino, Hematology 1, AOU “Città della salute e
della scienza di Torino”, Torino, Italy,
2
Division of Hematology,
Department of Translational Medicine, Università del Piemonte Orientale,
Novara, Italy,
3
Institute of Oncology Research, Faculty of Biomedical
Sciences, USI, Bellinzona, SIB Swiss Institute of Bioinformatics, Lausanne,
Switzerland,
4
Hematology and Cell Therapy Unit, IRCCS Istituto Tumori
'Giovanni Paolo II', Bari, Italy,
5
Institute of Oncology Research, Faculty of
Biomedical Sciences, USI, Bellinzona, Switzerland,
6
Hematology,
Department of Molecular Biotechnologies and Health Sciences, University
of Torino, Torino, Italy,
7
Unit of Cancer Epidemiology, CPO Piemonte, A.O.
U. Città della Salute e della Scienza di Torino, Torino, Italy,
8
Department
of Medical and Surgical Sciences, Section of Hematology, University of
Modena and Reggio Emilia, Azienda Ospedaliero Universitaria Policlinico,
Modena, Italy,
9
Hematology Department, AO “BianchiMelacrinoMorelli”,
Reggio Calabria, Italy,
10
Hematology Unit, General Hospital Ca' Foncello,
Treviso, Italy,
11
Hematology University Division, Verona Hospital, Verona,
Italy,
12
Department of Haematology and CBMT, Bolzano Hospital,
Bolzano, Italy,
13
Haematology Unit, ASST Monza San Gerardo, Monza,
Italy,
14
Hematology Unit, Azienda Ospedaliera SS Antonio e Biagio e
Cesare Arrigo, Alessandria, Italy,
15
Department of Hematology, S. Croce e
Carle Hospital, Cuneo, Italy,
16
UOC Ematologia e Trapianto, Az. Osp. C.
Panico, Tricase, Italy,
17
Section of Hematology, Department of Clinical
and Experimental Medicine, University of Pisa, Pisa, Italy,
18
Haematology
and Bone Marrow Transplant Unit, Parma General Hospital, Parma, Italy,
19
Institute of Oncology Research, Faculty of Biomedical Sciences, USI,
Bellinzona, Switzerland, Oncology Institute of Southern Switzerland (IOSI),
Bellinzona, Bellinzona, Switzerland,
20
Oncology Unit, Italy Medical &
Center Hospital Humanitas Gavazzeni and Castelli, Bergamo, Italy,
21
Division of Hematology, Department of Translational Medicine,
Università del Piemonte Orientale, Novara, Division of Hematology,
FIGURE 1
SUPPLEMENT ABSTRACTS
-
103
Azienda Ospedaliera SS Antonio e Biagio e Cesare Arrigo, Alessandria,
Italy
Introduction: TP53 and KMT2D disruptions, as well as high risk MIPI
c were independent prognosticators for younger mantle cell lym-
phoma (MCL) patients enrolled in the FIL MCL0208 trial
(NCT02354313, upfront high dose immunechemotherapy and
autologous transplantation, ASCT, followed by randomized lenalido-
mide maintenance) and were thus integrated in the MIPIg prog-
nostic model [Ferrero, 2020]. Furthermore, MCL is characterized by
many copy number variations (CNVs), whose clinical impact is not
clearly understood. This study aimed at refining the MIPIg model by
incorporating CNVs.
Methods: DNA from bone marrow CD19+sorted cells was pro-
filed with the Illumina HumanOmni2.5 array in 165 patients.
Minimal common regions were identified by bioinformatic pipeline
and smaller regions with GISTIC algorithm: both were considered
as CNVs. Progression free survival (PFS) was the primary endpoint.
Results: 351 CNVs were identified in at least one patient. Besides
TP53 deletion (already included in MIPIg) 10 further CNVs
showed predictive by univariate analysis and were selected for
multivariate Cox modelling (multiple comparisons were corrected
by Bonferroni). Actually, 4 CNVs maintained independent associa-
tion with PFS: Loss@chr22 in 10/165 (6%) patients with a HR of
4.14 (p =0.028), LOH@chr17 in 5 (3%) with a HR of 4.79 (p =
0.010), HDEL@chr9 in 3 (2%) with a HR of 18.1 (p =0.001) and
CDKN2A loss in 30 (18%) with a HR of 2.6 (p =0.002). Patients
with at least one of these 4 CNVs had 3y PFS of 34% compared
to 80% for wild type (WT) (p <0.001) and 3y overall survival (OS)
of 66% compared to 93% for WT (p <0.001). By using the same
approach employed for the MIPIg, we assigned a score to each
single predictor based on the Cox regression analysis. KMT2D
mutations (HR 2.43, 95% CI 1.214.87, p =0.012) TP53
disruptions (HR 2.63, 95% CI 1.385.02, p =0.003) and 4CNVs
(HR 2.56, 95% CI 1.434.61, p =0.002) had superimposable HRs
for PFS and thus scored 1 point. Interestingly, MIPIc high risk
class lost its independent prognostic value (HR 1.42, 95% CI 0.65
3.12, p =0.382), thus scoring 0 points. Consequently, a novel
“geneticsonly” model was developed, with patients grouped into 3
risk classes: i) 0 points, low risk group (LR =97, 60%); ii) 1 point,
intermediate risk (IR =41, 26%); iii) >2 points, high risk (HR =22,
14%). 3y PFS for LR, IR and HR was 86%, 50% and 24%,
respectively (p <0.0001, Fig 1A). The novel genetic score
improved the model discrimination ability, with a Cstatistics of
0.715 as compared to 0.675 for MIPIg. Interestingly, this model
was highly promising in terms of OS, too: actually, 3y OS for LR,
IR and HR was 92%, 74% and 59%, respectively (Fig 1B).
Discussion: The inclusion of 4CNVs into the MIPIg allowed the
development of a completely molecular model that improved the
stratification in MCL, enriching the HR group of patients, primary
refractory or destined to an early relapse after high dose chemo-
therapy and ASCT.
Keywords: Risk Models, Diagnostic and Prognostic Biomarkers,
Aggressive Bcell nonHodgkin lymphoma
No conflicts of interests pertinent to the abstract.
060 |EFFICACY AND SAFETY OF IBRUTINIB IN COMBINATION
WITH RITUXIMAB AS FRONTLINE TREATMENT FOR INDOLENT
CLINICAL FORMS OF MANTLE CELL LYMPHOMA. RESULTS OF
THE GELTAMO IMCL2015 STUDY
E. Giné
1
, F. De la Cruz
2
, A. Jiménez Ubieto
3
, J. López Jiménez
4
,
A. Martín GarcíaSancho
5
, M. J. Terol
6
, E. GonzálezBarca
7
,
M. Casanova
8
, A. De la Fuente Burguera
9
, A. Marín Niebla
10
,
FIGURE 1 PFS (A) and OS (B) according to the novel geneticsonly score
104
-
SUPPLEMENT ABSTRACTS
A. Muntanola Prat
11
, T. J. GonzálezLópez
12
, M. Aymerich
13
,
X. Setoain
14
, M. CortésRomera
15
, A. Rotger
16
A. Medina
5
,
R. GarcíaSanz
5
, E. Campo
17
, A. LópezGuillermo
18
1
Hospital Clínic of Barcelona, IDIBAPS, CIBERONC, Hematology,
Barcelona, Spain,
2
Hospital Universitario Virgen del Rocio, Hematology,
Sevilla, Spain,
3
Hospital Universitario 12 de Octubre, Hematology,
Madrid, Spain,
4
Hospital Universitario Ramón y Cajal, Hematology,
Madrid, Spain,
5
Hospital Clínico Universitario Salamanca, IBSAL,
CIBERONC, Hematology, Salamanca, Spain,
6
Hospital Universitario
Clínic de Valencia, INCLIVA, Hematology, Valencia, Spain,
7
Hospital
Duran i Reynals, ICO, IDIBELL, Hematology, Hospitalet de Llobregat,
Spain,
8
Hospital Costa del Sol, Hematology, Marbella, Spain,
9
MD
Anderson Cancer Center, Hematology, Madrid, Spain,
10
Hospital
Universitari Vall d'Hebrón, Hematology, Barcelona, Spain,
11
Hospital
Mútua de Terrassa, Hematology, Terrassa, Spain,
12
Hospital
Universitario de Burgos, Hematology, Burgos, Spain,
13
Hospital Clínic of
Barcelona, Hematopathology Unit, Barcelona, Spain,
14
Hospital Clínic of
Barcelona, Nuclear Medicine, Barcelona, Spain,
15
Hospital Universitari
de Bellvitge, Nuclear Medicine, Hospitalet de Llobregat, Spain,
16
Hospital General Universitario Gregorio Marañón, Nuclear Medicine,
Madrid, Spain,
17
Hospital Clínic of Barcelona, IDIBAPS, CIBERONC,
Universitat de Barcelona, Hematopathology Unit, Barcelona, Spain,
18
Hospital Clínic of Barcelona, IDIBAPS, CIBERONC, Universitat de
Barcelona, Hematology, Barcelona, Spain
SUPPLEMENT ABSTRACTS
-
105
Introduction: Mantlecell lymphoma (MCL) is a heterogeneous dis-
ease and the existence of indolent clinical forms is increasingly
recognized. The aim of this study was to propose a frontline tailored
treatment for indolent clinical forms with ibrutinib in combination
with rituximab (IR).
Methods: This is a multicenter singlearm, openlabel, phase II
study with a twostage design conducted in 14 Spanish GELTAMO
sites (NCT02682641). Centralized histology, PETCT review,
minimal residual disease (MRD) studies (qPCR and NGS in pe-
ripheral blood [PB] and bone marrow [BM]) and biological studies
are conducted. Previously untreated MCL patients with indolent
clinical forms were eligible according to the following criteria: no
symptoms attributable to MCL, ECOG 01, stable disease without
therapy need for at least 3 months, nonblastoid variants, Ki67
<30% and largest tumor diameter 3 cm. Both leukemic non
nodal and nodal forms were acceptable. Patients received
ibrutinib 560 mg daily and a total of 8 doses of rituximab 375
mg/m2 (4 weekly doses during the first 28day cycle, followed
by day 1 of cycles 3, 5, 7 and 9). Ibrutinib could be discontinued
after 2 years of treatment in case of sustained undetectable
MRD. The primary endpoint was the rate of complete re-
missions (CR) achieved after 12 cycles according to the Lugano
criteria.
Results: Fifty patients (Male 66%; median age 65 years) were
enrolled in the study (June 2016 to December 2019, data cutoff 22
Jan 2021, median followup 33 months). Efficacy data of the 50 pa-
tients included four cases that were discontinued earlier due to
adverse events (AE): ORR 84% and CR 80%. Regarding MRD evalu-
able cases (N =45), 86% achieved undetectable MRD in PB and 64%
also in BM. In CR cases, 72% had undetectable MRD in both PB and
BM.
After 24 months of treatment, 19 patients were in response with
undetectable MRD and discontinued ibrutinib treatment according
to protocol. Four patients progressed from the disease at 12, 38,
40 and 52 months of followup and two of them eventually died of
progression. Overall, PFS and OS estimated at 42 months were
81% (95% CI: 6598) and 86% (95% CI: 71100), respectively. Five
patients were withdrawn from the study due to serious adverse
events (one each), including skin rash, severe aplastic anemia,
pancreatic adenocarcinoma, and lumbar fractures, or by decision of
the patient. The most common treatmentrelated adverse events
(AE) were diarrhea (38%), neutropenia (36%), fatigue (32%), upper
respiratory infection (26%) nausea (22%), and arterial hypertension
(20%). AE grades 34 corresponded predominantly to hemato-
logic toxicity (22%). So far 10/50 patients have discontinued
ibrutinib due to intolerance.
Conclusion: In indolent clinical forms of MCL frontline ibrutinib in
combination with rituximab has a high efficacy, including unde-
tectable MRD in the majority of cases, with a predictable toxicity
profile.
The research was funded by: Janssen Clinical InvestigatorInitiated
Study (IIS) Research Support
Keywords: Aggressive Bcell nonHodgkin lymphoma, Molecular
Targeted Therapies
Conflicts of interests pertinent to the abstract
E. Giné
Consultant or advisory role: Gilead
Honoraria: Janssen, Gilead, Roche, Genmab
Research funding: Janssen, Gilead, Roche
Educational grants: Janssen, Gilead
061 |THE COMBINATION OF VENETOCLAX, LENALIDOMIDE
AND RITUXIMAB IN PATIENTS WITH NEWLY DIAGNOSED
MANTLE CELL LYMPHOMA INDUCES HIGH RESPONSE RATES
AND MRD UNDETECTABILITY
T. J. Phillips
1
, D. Bond
2
, S. Devata
3
, A. Danilov
4
, A. Herrera
4
,
K. Maddocks
2
, R. Wilcox
1
, Y. Karimi
1
, S. Carty
1
, M. Kaminski
1
,
L. Popplewell
4
1
University of Michigan, HematologyOncology, Ann Arbor, USA,
2
Ohio
State University, Hematology/Oncology, Columbus, USA,
3
Medical College
of Wisconsin, Hematology/Oncology, Milwaukee, USA,
4
City of Hope,
Hematology/Oncology, Duarte, USA
Background: MCL is a rare lymphoma without a standard of care but
several regimens have demonstrated clinical activity, the majority
based on traditional chemotherapy. We hypothesized that adding
venetoclax (V) to R2 would be safe and effective in MCL pts irre-
spective of age, morphology or stage. Here we present safety and
efficacy data from the ongoing phase 1b study of R2 +V in pts with
newly diagnosed MCL.
Methods: This multicenter phase 1 study (NCT03523975)
enrolled pts aged 18 yrs with untreated MCL. The primary
objective was to characterize the safety and tolerability of R2 +V
and determine the MTD. During induction (12 months (m)) pts
received lenalidomide (L) 20 mg daily on day 121, Rituximab (R)
was given weekly during c1 then on day 1 of every even cycle, V
was escalated over 4 weeks to 400 mg beginning day 8. Each cycle
is 28 days (d). The DLT period was 42 d beginning C1D8. In
maintenance, R every 8 weeks for 36m, L at 10 mg or half of last
dose during induction for 24 m and V for minimum 12 m. No pts
have been transplanted. Pts with progression (PD) came off study.
MRD was analyzed in parallel with scans during induction by
clonoSEQ assay (Adaptive Biotechnologies).
Results: As of Feb. 1st, 2021, we have enrolled all 28 planned pts
on study. Pt characteristics/responses are summarized in Table 1.
Among the 28 pts who have received at least one dose, the
106
-
SUPPLEMENT ABSTRACTS
median treatment duration so far is 278d (IQR 170560), with
24 pts still on treatment (Tx). 1 pt is off from a unrelated
condition.
All pts escalated to V 400 mg w/o any DLTs noted. Treatment
emergent adverse events (TEAEs) were reported in 100% of pts,
and grade 3+TEAEs were reported in 26 (93%) patients. The most
common allgrade TEAEs (50% of pts), regardless of relationship to
study Tx, were fatigue, neutropenia and diarrhea. Grade 3 TEAEs
reported in 50% pts were neutropenia (68%) and thrombocytopenia
(50%). No pts have withdrawn or d/c Tx due to AEs. There was one
grade 5 event, in a nonevaluable pt, related to a PE that occurred
prior to DLT period.
In the 28 evaluable pts the ORR (CR/PR) was 96% (27/28 pts) with
CR/CRu of 89%. Of the responding pts, two had PD, one w/ CR and
one w/ PR. All pts with PD had baseline TP53 mutation. MRD testing
was successful in all pts. At time of submission 20 of 28 (71%) were
MRD at 10
6
.
Conclusions: Interim results show that at the MTD the combina-
tion of V 400 mg daily, L 20 mg, with R is safe with a manageable
toxicity profile and a high ORR and MRD in pts with
newly diagnosed MCL. Safety data is consistent with the AE profile
noted for each drug without any unexpected or unique AEs.
Updated results including BH3 profiling will be presented at the
meeting.
EA previously submitted to ASCO 2021
The research was funded by: Abbvie,Rogel Cancer Center, BMS (drug
only)
Keywords: Aggressive Bcell nonHodgkin lymphoma, Combination
Therapies, Ongoing Trials
Conflicts of interests pertinent to the abstract
T. J. Phillips
Consultant or advisory role: Abbvie, BMS, Genentech, TG thera-
peutics, Gilead, Bayer, Incyte, ADCT therapeutics,
Research funding: AbbVie, Bayer, BMS
062 |SAKK 36/13 IBRUTINIB PLUS BORTEZOMIB AND
IBRUTINIB MAINTENANCE FOR RELAPSED AND REFRACTORY
MANTLE CELL LYMPHOMA: FINAL REPORT OF A PHASE I/II
TRIAL OF THE EUROPEAN MCL NETWORK
U. Novak
1
, M. Fehr
2
, S. Schär
3
, M. Dreyling
4
, G. Scheubeck
4
,
S. Ramadan
5
, E. Zucca
6
, T. Zander
7
, G. Hess
8
, U. Mey
9
, S. Ferrero
10
,
N. Mach
11
, C. Boccomini
10
, S. Böttcher
12
, M. Voegeli
13
, A. Cairoli
14
,
T. Menter
15
, S. Dirnhofer
15
, S. Gadient
3
, K. Eckhardt
3
, C. Driessen
2
,
C. Renner
16
1
Inselspital, Bern University Hospital, Medical Oncology, Bern,
Switzerland,
2
Kantonsspital St. Gallen, Department of Medical Oncology
and Hematology, St. Gallen, Switzerland,
3
SAKK, Coordinating Center,
Bern, Switzerland,
4
Universität MünchenGrossadern, Medizinische Klinik
III, München, Germany,
5
IEO, European Institute of Oncology IRCCS,
OncoHematology Division, Milano, Italy,
6
Oncology Institute of Southern
Switzerland, Ospedale San Giovanni, Bellinzona, Switzerland,
7
Kant-
onsspital Luzern, Department Oncology, Luzern, Switzerland,
8
Johannes
Gutenberg Universität Mainz, Universitätsmedizin, Mainz, Germany,
9
Kantonsspital Graubünden, Department of Oncology and Hematology,
Chur, Switzerland,
10
AOU “Città della Salute e della Scienza di Torino”,
Hematology 1, Torino, Italy,
11
University Hospital of Geneva, Department
of Oncology, Genève, Switzerland,
12
Rostock University Medical Center,
Department of Medicine, Clinic III Hematology, Oncology, Palliative
Medicine, Rostock, Germany,
13
Kantonsspital Baselland, Oncology, Liestal,
Switzerland,
14
CHUV University Hospital and University of Lausanne,
Service et Laboratoire Central d'Hématologie, Département d'Oncologie,
Lausanne, Switzerland,
15
University Hospital Basel, Institute of Pathology
and Medical Genetics, Basel, Switzerland,
16
Onkozentrum, Hirslanden &
Zürich, Zürich, Switzerland
Introduction: Mantlecell lymphoma (MCL) remains incurable with
frequent relapses, limited treatment options and progressively
shorter diseasefree survival with every relapse. The Bruton's
tyrosine kinase inhibitor ibrutinib (IBR) and the proteasome in-
hibitor bortezomib (BOR) have single agent activity and regulatory
approval in MCL. IBR and BOR lead to a downregulation of NF‐κB
activity via different targets. IBR resistance involves mutations in
genes of the NF‐κB pathway. In vitro, the combination of both
drugs provides synergistic cytotoxicity in BORsensitive and re-
fractory MCL.
Methods: In this investigatorinitiated trial, we included patients
(pts.) with histologically confirmed MCL, refractory/relapsed after 2
lines of a nonBORcontaining chemotherapy (incl. highdose
chemotherapy), and excluded pts. with prior BOR or IBR therapy,
with CNS disease, in need of anticoagulation, or active Hepatitis B, C
or HIV infection. Pts. received 6 21days cycles of IBR +BOR, fol-
lowed by IBR until progression or unacceptable toxicity. The dose of
the combination was established with 9 pts. in the phase I part: BOR
s.c. 1.3 mg/m
2
, days 1, 4, 8, 11 q3w, and IBR continuously at 560 mg/
day. The primary endpoint of the phase II was the overall response
rate (ORR) based on CT/MRI (Cheson, 1999). The null hypothesis was
TABLE 1
Sex, male, % (n) 64% (18)
Age, years, median (IQR) 65 (57, 69)
Race, white, % (n) 100% (28)
Tx duration, d, median (IQR) 278 (170, 560)
Stage IV, % (n) 96% (27)
MIPI High, % (n) 64% (18)
Blast/Pleo, % (n) 21% (6)
Ki67 30%, % (n) 68% (19)
ORR 96%
CR/CRu 89%
MRD 71%
SUPPLEMENT ABSTRACTS
-
107
an OR 65%. Data on secondary endpoints were collected until
January 18, 2021.
Results: Since August 2015, 58 pts. received IBR+BOR (9 in
phase I (4 Swiss sites), and 49 in 11 additional sites in
Switzerland, Germany and Italy). The median age was 71 (4790),
78% were male. The ORR in 55 pts. (including those that received
560 mg IBR in phase I) to the combination was 81.8% (90% CI
71.1, 89.8%, CR(u) 21.9%). With continued IBR (median 6 months
(M)), the ORR increased to 87.3% (90% CI 77.4, 93.9%, CR(u)
43.7%). 31/55 pts. (56.4%) had at least one highrisk feature. In
these, IBR+BOR was also effective (ORR 79% (90% CI 62, 90%),
n=28) for Ki67 >30%, ORR 73% (90% CI 44, 92), n =11) for
p53 overexpression by immunohistochemistry (>50%, suggestive
for mutations), and 67% (90% CI 34, 90%), n =9) for the blas-
toid/pleomorphic variants), and not different in terms of time to
best response from pts. with low risk features. With a me-
dian followup of 24.4M, the median duration of response was
22.7M (95% CI 12.3, NA), and the median PFS was 18.6M
(95% 12.4, NA). All pts. had at least one adverse event (AE),
which was grade (G)3 in 67.3%, and G4 in 21.8%. G3 infections
(25%) and G4 hematotoxicity (16.4%) were the most frequent AEs
during the combination. Neurotoxicity, mostly G1&2 occurred in
14.5%.
Conclusions: The combination of Ibrutinib and Bortezomib shows
significant and durable efficacy in relapsed mantlecell lymphoma,
importantly also in patients with highrisk features. In this setting,
this regimen is a rational comparator regimen for a future phase III
trial.
(ClinicalTrials.gov Identifier: NCT02356458)
The research was funded by: JanssenCilag
Keywords: Combination Therapies
Conflicts of interests pertinent to the abstract
U. Novak
Consultant or advisory role: JanssenCilag, Celgene (BMS), Takeda,
Astra Zeneca, Roche, Novartis, Gilead, Pierre Fabre
Honoraria: Celgene (BMS), Novartis
M. Dreyling
Consultant or advisory role: Astra Zeneca, Bayer, Beigene, Celgene,
Gilead, Janssen, Novartis, Roche
Honoraria: Bayer, Celgene, Gilead, Janssen, Roche
Research funding: Abbvie, Bayer, Celgene, Janssen, Roche
U. Mey
Consultant or advisory role: JanssenCilag
S. Ferrero
Consultant or advisory role: Janssen
Honoraria: Janssen
Research funding: Janssen
S. Böttcher
Honoraria: Roche, AbbVie, Janssen, AstraZeneca, Sanofi
Research funding: JanssenCilag Neuss, Becton Dickinson
Heidelberg
C. Renner
Consultant or advisory role: JanssenCilag
Honoraria: JanssenCilag
063 |INDUCTION R
2
FOLLOWED BY MAINTENANCE IN
PATIENTS WITH RELAPSED/REFRACTORY MANTLE CELL
LYMPHOMA: INTERIM ANALYSIS FROM THE PHASE 3B
MAGNIFY STUDY
J. P. Sharman
1
, J. M. Melear
2
, A. Yacoub
3
, S. R. Fanning
4
,
D. J. Andorsky
5
, G. S. Nowakowski
6
, M. J. Rummel
7
, F. Lansigan
8
,
J. Li
9
, J. R. Ahn
10
, M. Gharibo
10
, M. Coleman
11
1
Willamette Valley Cancer Institute and Research Center, US Oncology
Research, Eugene, Oregon, USA,
2
Texas OncologyAustin, US Oncology
Research, Austin, USA,
3
University of Kansas Cancer Center, Depart-
ment of HematologyOncology, Westwood, USA,
4
Prisma Health, US
Oncology Research, Greenville, USA,
5
Rocky Mountain Cancer Centers,
US Oncology Research, Boulder, USA,
6
Mayo Clinic, Division of He-
matology, Rochester, USA,
7
JustusLiebig Universität, Med. Clinic IV,
Hematology, Giessen, Germany,
8
DartmouthHitchcock Medical Center,
Division of Hematology and Oncology, Lebanon, USA,
9
Bristol Myers
Squibb, Global Biometrics and Data Sciences, Princeton, New Jersey,
USA,
10
Bristol Myers Squibb, US Medical Affairs Hematology, Princeton,
New Jersey, USA,
11
Clinical Research Alliance Inc, Weill Cornell Med-
icine, New York, USA
Background: The combination of lenalidomide +rituximab (R
2
) has
shown complementary clinical activity and is a tolerable regimen in
both untreated and relapsed or refractory (R/R) indolent non
Hodgkin lymphoma (NHL), as well as mantle cell lymphoma (MCL),
an uncommon but aggressive form of NHL.
Methods: MAGNIFY is a multicenter, phase 3b trial (NCT01996865)
in patients with R/R follicular lymphoma (FL) grades 1—3b, trans-
formed FL, marginal zone lymphoma, and MCL. Lenalidomide 20 mg
on d 1—21 of a 28d cycle +rituximab 375 mg/m
2
/wk cycle 1 and
then every 8 wk starting with cycle 3 (R
2
) is given for 12 cycles
followed by 1:1 randomization in patients with stable disease, partial
response, or complete response/complete response unconfirmed
(CR/CRu) to R
2
vs rituximab maintenance for 18 mo. The primary end
point is progressionfree survival (PFS) by 1999 International
Working Group (IWG) criteria. Secondary end points include safety,
CR rate, duration of response (DOR), duration of CR (DOCR), time
toresponse (TTR), timetonext antilymphoma therapy, and overall
survival. This analysis evaluates the interim primary endpoint of
overall response rate (ORR) by 1999 IWG criteria and safety of R
2
108
-
SUPPLEMENT ABSTRACTS
induction in patients with MCL in the induction intentiontotreat
population.
Results: As of August 28, 2020, 73 patients with MCL were
enrolled (median age, 70.0 y [range, 5188]); 89% had stage III/IV
disease, and 41% had bulky disease (>7 cm or >3 cm 3 lymph
nodes). All patients had received prior rituximabcontaining ther-
apy, with 25 (34%) rituximab refractory (progression 6 mo after
last rituximab dose). Seven patients (10%) had received prior
ibrutinib. Median followup was 31.7 mo for patients still alive.
ORR was 51%, with 34% CR rate (CR +CRu), irrespective of prior
refractory status to rituximab (Table). Median DOR was 31.6 mo;
median DOCR was not reached; median TTR was 2.8 mo, and
median PFS was 28.0 mo, with 1year PFS rate of 57%. The most
common treatment emergent adverse events (TEAEs) of any grade
were neutropenia (51%), fatigue (44%), diarrhea (32%), con-
stipation (28%), cough (28%), dyspnea (26%), and nausea (26%).
Grade 3/4 neutropenia was 46%; all other grade 3/4 TEAEs were
11%.
Conclusions: R
2
is an active and tolerated regimen with durable re-
sponses among patients with R/R MCL and mostly naive to Bruton
tyrosine kinase inhibitor therapy.
Keywords: Aggressive Bcell nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
J. P. Sharman
Consultant or advisory role: Abbvie; Acerta Pharma; BMS; Celgene;
Pharmacyclics; TG Therapeutics
Research funding: Acerta Pharma; Celgene; Pharmacyclics; TG
Therapeutics
J. M. Melear
Other remuneration: Speaker's Bureau: AstraZeneca, Janssen
A. Yacoub
Other remuneration: Speaker's Bureau: Incyte
S. R. Fanning
Stock ownership: BMS, Abbvie, TG Pharma
Honoraria: BMS, Takeda, Abbvie, TG Pharma
Other remuneration: SPEAKER's BUREAU: BMS, Takeda, Sanofi
D. J. Andorsky
Consultant or advisory role: Abbvie, BMS
Research funding: Celgene, AstraZeneca, Epizyme
G. S. Nowakowski
Consultant or advisory role: Selvita, Debiopharm Group, Kite/Gilead,
Celgene, MorphoSys, Genentech
Research funding: Celgene, NanoString Technologies, MorphoSys
F. Lansigan
Consultant or advisory role: Celgene/BMS
Honoraria: Celgene/BMS
Research funding: Acrotech Pharmaceuticals
J. Li
Employment or leadership position: BMS
Stock ownership: BMS
Research funding: BMS
Educational grants: BMS
J. R. Ahn
Stock ownership: BMS
M. Gharibo
Stock ownership: BMS
M. Coleman
Stock ownership: immunomedics
Research funding: Abbvie, Bristol Myers, Celgene, Genentech, Gilead,
BeiGene, Innocare, Merck, Pfzier, Roche
TABLE 1Efficacy for induction R
2
in patients with R/R MCL in MAGNIFY
SUPPLEMENT ABSTRACTS
-
109
SESSION 10: LYMPHOMA BIOLOGY 2
064 |THE TOPOLOGY OF MYC REARRANGEMENTS IN
DOUBLEHIT LYMPHOMA IS CONSTRAINED BY THE
PRECEDING IGHBCL2 REARRANGEMENT AN LLMPP
PROJECT
L. K. Hilton
1
, B. Collinge
1
, S. BenNeriah
1
, B. M. Grande
2
, G. W.
Slack
1
, P. Farinha
1
, T. MiyataTakata
3
, J. R. Cook
4
, G. Ott
5
,
A. Rosenwald
6
, E. Campo
7
, C. Amador
8
, T. C. Greiner
8
, P. W.
Raess
9
, J. Y. Song
10
, G. Inghirami
11
, E. S. Jaffe
12
, D. D. Weisen-
burger
10
, W. C. Chan
10
, H. Holte
13
, K. Beiske
14
, K. Fu
15
, J. Dela-
bie
16
, S. Pittaluga
12
, A. L. Feldman
17
, L. H. Sehn
1
, K. J. Savage
1
,
A. J. Mungall
18
, L. M. Staudt
19
, C. Steidl
1
, L. M. Rimsza
20
, R. D.
Morin
21
, D. W. Scott
1
1
BC Cancer, Centre for Lymphoid Cancer, Vancouver, Canada,
2
Sage
Bionetworks, Seattle, Washington, USA,
3
Niigata University Graduate
School of Medical and Dental Sciences, Division of Molecular and
Cellular Pathology, Niigata, Japan,
4
Cleveland Clinic, Department of
Molecular Pathology and Laboratory Medicine, Cleveland, Ohio, USA,
5
RobertBoschKrankenhaus and Dr. Margarete FischerBosch Institute
of Clinical Pharmacology, Department of Clinical Pathology, Stuttgart,
Germany,
6
University of Wuerzburg, Institute of Pathology, Wuerzburg,
Germany,
7
Hospital Clinic, Department of Pathology, Barcelona, Spain,
8
University of Nebraska Medical Center, Department of Pathology and
Microbiology, Omaha, Nebraska, USA,
9
Oregon Health & Science Uni-
versity, Department of Pathology, Portland, Oregon, USA,
10
City of
Hope National Medical Center, Department of Pathology, Duarte, Cal-
ifornia, USA,
11
Weill Cornell Medicine, Pathology and Laboratory
Medicine, New York, New York, USA,
12
National Cancer Institute,
Laboratory of Pathology, Bethesda, Maryland, USA,
13
Oslo University
Hospital, Department of Oncology, Oslo, Norway,
14
Oslo University
Hospital, Department of Pathology, Oslo, Norway,
15
Roswell Park
Cancer Institute, Department of Pathology & Laboratory Medicine,
Buffalo, New York, USA,
16
University Health Network and University of
Toronto, Department of Laboratory Medicine and Pathobiology, Tor-
onto, Canada,
17
Mayo Clinic College of Medicine, Laboratory Medicine
and Pathology, Rochester, Minnesota, USA,
18
Canada's Michael Smith
Genome Sciences Centre, BC Cancer Research Institute, Vancouver,
Canada,
19
National Cancer Institute, Center for Cancer Research,
Bethesda, Maryland, USA,
20
Mayo Clinic Arizona, Department of Lab-
oratory Medicine and Pathology, Scottsdale, Arizona, USA,
21
Simon
Fraser University, Molecular Biology and Biochemistry, Burnaby,
Canada
Introduction: Highgrade Bcell lymphoma with MYC and BCL2 and/
or BCL6 rearrangements (HGBLDH/TH) are aggressive tumors with
poor prognosis. In virtually all HGBLDH/THBCL2 tumors, BCL2 is
rearranged to the variable region of the IGH locus, which is thought
to occur early in Bcell differentiation during RAGmediated VDJ
recombination, leading to constitutive overexpression of BCL2 driven
by the potent IGH Eµenhancer. We explored the topology of MYC
rearrangements in doublehit lymphomas compared with Burkitt
lymphoma (BL) and MYC singlehit diffuse large Bcell lymphoma
(DLBCL), to reveal patterns imposed by the preceding IGHBCL2
rearrangement.
Methods: We identified 112 HGBLDH/THBCL2 and 55 de novo
DLBCL MYC singlehit by breakapart fluorescence in situ hybrid-
ization, and included 96 MYCrearranged BL tumors as a com-
parison group. A combination of whole genome and capture
sequencing was used to identify MYC, BCL2 and BCL6 breakpoint
sequences. Sequencing data were aligned to hg38 with bwamem,
and structural variants were called using Manta, GRIDSS, and
Delly. RNAseq data were quantified with Salmon and normalized
with variance stabilizing transformation to interrogate MYC
expression levels.
Results: The MYC breakpoint sequence was recovered in 77% of
tumors. Among BL and singlehit DLBCL tumors, over 80% of MYC
rearrangements have an IGH partner, and less than 10% are part-
nered with IGL, IGK, or nonIG loci (Figure 1). In contrast, only 35% of
MYC rearrangements in HGBLDH/THBCL2 have an IGH partner,
while 21% have IGL and 40% have nonIG partners (Figure 1). We
show that MYC expression is comparable among all IG and most
recurrent nonIG partners. Strikingly, in HGBLDH/THBCL2 with
IGHMYC, the rearrangement involved the previously rearranged
IGHBCL2 allele, and the breakpoints exclusively localized to the
recipient switch regions. This rearrangement leaves an intact Eµ
enhancer in proximity to BCL2 on a doubly rearranged IGH allele
while leaving the second IGH allele intact. In contrast, in BL and
singlehit DLBCL the IGHMYC breaks were equally distributed to Sµ
(the donor IGHM switch region) and the recipient switch regions.
MYC expression was equivalent in tumors with Sµand recipient
switch region breakpoints.
Conclusions: This study demonstrates that the pattern of MYC
rearrangements in HGBLDH/THBCL2 is constrained by the pres-
ence of IGHBCL2.MYC is infrequently rearranged to the IG variable
regions, supporting that MYC translocation is a class switchrelated
event that occurs later in lymphomagenesis. The observed MYC
rearrangements preserve both an intact IGH allele and the rela-
tionship between BCL2 and the IGH Eµenhancer. This leads to the
hypothesis that, at the time of acquiring the MYC rearrangement,
tumor survival is contingent on both intact Bcell receptor expression
and the antiapoptotic activity of BCL2.
Keywords: Genomics, Epigenomics, and Other Omics, Aggressive B
cell nonHodgkin lymphoma, Pathology and Classification of
Lymphomas
No conflicts of interests pertinent to the abstract.
110
-
SUPPLEMENT ABSTRACTS
065 |THE MUTATIONAL LANDSCAPE OF DOUBLE/TRIPLEHIT
HIGHGRADE BCELL LYMPHOMA WITH BCL2
REARRANGEMENT (DH/THBCL2) AN LLMPP PROJECT
B. J. Collinge
1
, L. K. Hilton
1
, J. Wong
1
, S. BenNeriah
1
, W. Alduaij
1
,
C. K. Rushton
2
, G. W. Slack
1
, P. Farinha
1
, T. MiyataTakata
3
, J. R.
Cook
4
, G. Ott
5
, A. Rosenwald
6
, E. Campo
7
, C. Amador
8
, T. C. Greiner
8
,
P. W. Raess
9
, J. Y. Song
10
, G. Inghirami
11
, E. S. Jaffe
12
, D. D. Wei-
senburger
10
, W. C. Chan
10
, H. Holte
13
, K. Beiske
14
, K. Fu
15
, J. Dela-
bie
16
, S. Pittaluga
12
, A. L. Feldman
17
, L. H. Sehn
1
, K. J. Savage
1
,
A. J. Mungall
18
, L. M. Staudt
19
, C. Steidl
1
, L. M. Rimsza
20
, R. D. Morin
2
,
D. W. Scott
1
1
BC Cancer, Centre for Lymphoid Cancer, Vancouver, Canada,
2
Simon
Fraser University, Molecular Biology and Biochemistry, Burnaby,
Canada,
3
Niigata University Graduate School of Medical and Dental
Sciences, Division of Molecular and Cellular Pathology, Niigata, Japan,
4
Cleveland Clinic, Department of Molecular Pathology and Laboratory
Medicine, Cleveland, Ohio, USA,
5
RobertBoschKrankenhaus and Dr.
Margarete FischerBosch Institute of Clinical Pharmacology, Depart-
ment of Clinical Pathology, Stuttgart, Germany,
6
University of
Wuerzburg, Institute of Pathology, Wuerzburg, Germany,
7
Hospital
Clinic of the University of Barcelona, Department of Pathology, Bar-
celona, Spain,
8
University of Nebraska Medical Center, Department of
Pathology and Microbiology, Omaha, Nebraska, USA,
9
Oregon
Health & Science University, Department of Pathology, Portland,
Oregon, USA,
10
City of Hope National Medical Center, Department of
Pathology, Duarte, California, USA,
11
Weill Cornell Medicine, Pathology
and Laboratory Medicine, New York, New York, USA,
12
National
Cancer Institute, Laboratory of Pathology, Bethesda, Maryland, USA,
13
Oslo University Hospital, Department of Oncology, Oslo, Norway,
14
Oslo University Hospital, Department of Pathology, Oslo, Norway,
15
Roswell Park Cancer Institute, Department of Pathology & Labora-
tory Medicine, Buffalo, New York, USA,
16
University Health Network
and University of Toronto, Department of Laboratory Medicine and
Pathobiology, Toronto, Canada,
17
Mayo Clinic College of Medicine,
Laboratory Medicine and Pathology, Rochester, Minnesota, USA,
18
BC
Cancer, Canada's Michael Smith Genome Sciences Centre, Vancouver,
Canada,
19
National Cancer Institute, Center for Cancer Research,
Bethesda, Maryland, USA,
20
Mayo Clinic, Department of Laboratory
Medicine and Pathology, Scottsdale, Arizona, USA
Introduction: The poor outcome of highgrade Bcell lymphoma with
MYC and BCL2 and/or BCL6 rearrangement (DH/TH) highlights the
need for identifying specific targetable biology. Although a gene
expression signature (DHITsig) shared by DH/THBCL2 tumours has
confirmed a unified biology, the genetic features of these tumours
beyond MYC/BCL2 rearrangement are not well established. Here, we
explore the mutational landscape of DH/THBCL2 to identify key
molecular features that may inform on targetable tumour cell
vulnerabilities.
Methods: Diagnostic biopsies of 102 DH/THBCL2 tumours
(morphology: 60 diffuse large Bcell lymphoma (DLBCL); 42 high
grade intermediate or blastoid) were identified with break
apart fluorescent in situ hybridization (FISH). Tumours with
SUPPLEMENT ABSTRACTS
-
111
DLBCL morphology had no history of indolent lymphoma and were
sourced from BC Cancer where unbiased FISH testing was applied.
Among tumours of highgrade morphology, 29% had a history of
indolent lymphoma. High confidence somatic mutations (SNVs/
Indels) were identified on whole genome or exome sequencing
using an ensemble of variant callers (Strelka2, LoFreq, Mutect2,
SAGE). Mutation frequencies among recurrently mutated genes
were compared to Burkitt lymphoma (BL; Grande et al. Blood
2019) and GCB DHITsigneg DLBCL (Schmitz et al. NEJM 2018) to
identify genes with significant differences in the recurrence of non
silent mutations (FDR <0.05). Genetic subtypes were assigned
using the LymphGen data portal.
Results: The most frequently mutated genes in DH/THBCL2 were
in chromatin modifiers KMT2D,CREBBP, and EZH2, along with
BCL2 and TNFRSF14 genes commonly mutated in follicular
lymphoma (FL) and EZB DLBCL. Consistently, 92% of tumours
were classified as EZB by LymphGen. Comparisons of DH/TH
BCL2 to GCB DHITsigneg DLBCL revealed less frequent alter-
ations of genes involved in NF‐κB signaling and immune surveil-
lance. Mutations in germinal centre dark zone (DZ) regulatory
genes FOXO1 and CCND3 were more frequent in DH/THBCL2
genes that are also recurrently mutated in BL. While mutations in
NF‐κB signaling pathways and immune surveillance were also
uncommon in BL, these tumours were readily distinguishable from
DH/THBCL2 by the absence of “FLlike” mutations and more
frequent alterations to ID3,DDX3X,FBXO11,ARID1A, and
SMARCA4.
Conclusion: The similarity to FL is suggestive of an evolutionary
trajectory through an FL/FLlike common progenitor, where DH/TH
BCL2 diverges from this trajectory by adopting a DZlike identity.
This is supported by near universal DHITsig positivity of both DH/
THBCL2 and BL, suggesting this signature more accurately identifies
a DZ biology that may be at least partly promoted by MYC rear-
rangement and mutations in FOXO1 and CCND3. Infrequent muta-
tions promoting immune escape in DH/THBCL2 and BL is consistent
with a decreased selective pressure due to the “immune cold” nature
of the DZ.
Keywords: Genomics, Epigenomics, and Other Omics, Aggressive B
cell nonHodgkin lymphoma, Pathology and Classification of
Lymphomas
No conflicts of interests pertinent to the abstract.
066 |DO CELLOFORIGIN, DOUBLE EXPRESSER, AND
DOUBLE HIT STATUS AFFECT OUTCOMES IN RELAPSED/
REFRACTORY DIFFUSE LARGE B CELL LYMPHOMA
(R/R DLBCL)? A PROSPECTIVE OBSERVATIONAL STUDY
S. H. Desai
1
, R. Mwangi
2
, M. Maurer
3
, R. King
4
, J. Cerhan
2
,
A. Feldman
1
, T. Habermann
5
, U. Farooq
6
, C. Thompson
5
, Y. Wang
1
,
S. M. Ansell
1
, T. E. Witzig
1
, G. N. Nowakowski
5
1
Mayo Clinic, Division of Hematology, Department of Medicine, Rochester,
Minnesota, USA,
2
Mayo Clinic, Department of Quantitative Health
Sciences, Rochester, Minnesota, USA,
3
Mayo Clinic, Department of
Quantitative Health Sciences, Rochester, Minnesota, USA,
4
Mayo Clinic,
Department of Laboratory Medicine and Pathology, Rochester, Minnesota,
USA,
5
Mayo Clinic, Division of Hematology, Department of Medicine,
Rochester, Minnesota, USA,
6
University of Iowa Hospitals and Clinics,
Department of Hematology, Oncology and Bone Marrow Transplant, Iowa
City, Iowa, USA
Introduction: Gene expression profiling classifies DLBCL by cell of
origin (COO) into germinal center B cell (GCB) and activated B cell
(ABC) but a proportion of cases remain unclassified. Treatmentnaïve
GCBDLBCL have better outcomes. Double hit lymphoma (DHL)
defined as high grade B cell lymphoma with rearrangements of MYC
and BCL2 or BCL6, and double expressor lymphoma (DEL) defined as
DLBCL with coexpression of BCL2 and MYC proteins, have poor
outcomes with frontline treatment. Impact of COO, DHL and DEL
status in R/R DLBCL is also not wellcharacterized. We evaluated the
impact of these markers on outcomes of R/R DLBCL in a prospective
observational study.
Methods: Study cohort is derived from consecutive adult DLBCL
patients (pts) enrolled within 9 months of initial diagnosis into the
Molecular Epidemiology Resource (MER) cohort of the University of
Iowa/Mayo Clinic Lymphoma Specialized Program of Research
Excellence. Pts who relapsed after firstline therapy were included.
COO was available from immunohistochemistry (IHC) using Hans
algorithm and gene expression profiling (GEP) (Nanostring) on the
diagnostic FFPE biopsy. BCL2, MYC and BCL6 rearrangement were
done by FISH and protein expression was done by IHC. Pts were
followed for outcomes every 6 months from the date of diagnosis for
first 3 years and then annually thereafter. Study objective was overall
survival (OS) from first relapse.
Results: Of 373 pts with R/R DLBCL, 227 (61%) were male and
333 (93%) were white. At diagnosis, 278 (75%) had advanced
stage, 84 (23%) >1 extranodal sites, and 178 (48%) had interna-
tional prognostic index (IPI) 3. 278 pts had COO by IHC: 169
(60%) were GCB and 109 (40%) were nonGCB. 140 had COO by
Nanostring: 44 (31%) were ABC, 72 (52%) were GCB, 13 (9%)
were unclassified and 11(8%) failed assay. 19 (5%) were DHL and
354 (95%) were nonDHL. 34 (9%) had DEL, 115 (31%) were non
DEL and 224 did not have DEL status available. COO, either by
IHC [5 yr OS 31% (CI
95
: 2439) in GCB and 33% (CI
95
:2544) in
nonGCB] or Nanostring [5 yr OS 31% (CI
95
: 2244) in GCB, 25%
(CI
95
: 1443) in ABC, 39% (CI
95
: 1977) in unclassified], was not
associated with difference in OS (Fig 1AB). DHL [2 yr OS 16
(CI
95
:645) vs 43% (CI
95
: 3949), p <0.01] and DEL [5 yr OS 17%
(CI
95
: 839) vs 33% (CI
95
: 2543), p =0.01] had lower OS than
nonDHL and nonDEL (1C&D).
Conclusions: COO at diagnosis by IHC or GEP does not impact
outcome of R/R DLBCL while DHL and DEL status were associated
with worse outcomes in R/R setting. Hence, evolving molecular
112
-
SUPPLEMENT ABSTRACTS
signatures of DLBCL beyond COO and interaction with tumor
microenvironment may be more important drivers of pathophysi-
ology of R/R DLBCL. While pattern of relapse, resistance to
chemotherapy and efficacy of transplant need to be explored to
better characterize poor outcomes of R/R DHL and DEL, results of
this study will be helpful in design and interpretation of clinical
trials evaluating novel therapeutics in R/R DLBCL.
Keywords: Diagnostic and Prognostic Biomarkers, Aggressive Bcell
nonHodgkin lymphoma
No conflicts of interests pertinent to the abstract.
067 |COPY NUMBER VARIATION ANALYSIS IDENTIFIES
DISTINCT GENOMIC FEATURES IN ADULT BURKITT LYMPHOMA
K. Dreval
1
, N. Thomas
1
, D. S. Gerhard
2
, L. K. Hilton
3
, J. Wong
3
,
J. S. Abramson
4
, N. L. Bartlett
5
, J. Bethony
6
, J. Bowen
7
, A. C. Bryan
8
,
C. Casper
9
, M. Dyer
10
, J. M. GastierFoster
7
, B. M. Grande
11
,
T. Greiner
12
, N. B. Griner
2
, T. G. Gross
13
, N. L. Harris
14
, J. D. Irvin
15
,
E. Jaffe
16
, F. Leal
17
, J. P. Martin
15
, M.R. Martin
15
, S. M. Mbulaiteye
18
,
C. G. Mullighan
19
, A. J. Mungall
20
, K. Mungall
20
, C. Namirembe
21
,
A. Noy
22
, M. D. Ogwang
23
, J. Orem
21
, H. Petrello
7
, S. J. Reynolds
24
,
S. H. Swerdlow
25
, A. TraverseGlehen
26
, W. H. Wilson
27
,
M. A. Marra
20
, L. M. Staudt
27
, D. W. Scott
3
, R. D. Morin
1
1
Simon Fraser University, Department of Molecular Biology and
Biochemistry, Burnaby, Canada,
2
National Cancer Institute, National
Institutes of Health, Office of Cancer Genomics, Bethesda, Maryland,
USA,
3
BC Cancer, Centre for Lymphoid Cancer, Vancouver, Canada,
4
Massachusetts General Hospital, Harvard Medical School, Center for
Lymphoma, Boston, Massachusetts, USA,
5
Washington University,
School of Medicine, St. Louis, Missouri, USA,
6
George Washington
University, Department of Microbiology, Immunology, and Tropical
Medicine, Washington, District of Columbia, USA,
7
Nationwide
Children's Hospital, The Abigail Wexner Research Institute, Columbus,
Ohio, USA,
8
Nationwide Children's Hospital, Biopathology Center,
Columbus, Ohio, USA,
9
Infectious Disease Research Institute, Seattle,
Washington, USA,
10
Frederick National Laboratory for Cancer Research
sponsored by the National Cancer Institute, Clinical Research
Directorate, Frederick, Maryland, USA,
11
Sage Bionetworks, Seattle,
Washington, USA,
12
University of Nebraska Medical Center,
Department of Pathology and Microbiology, Omaha, Nebraska, USA,
13
National Cancer Institute, National Institutes of Health, Center for
Global Health, Rockville, Maryland, USA,
14
Massachusetts General
Hospital, Harvard Medical School, Department of Pathology, Boston,
Massachusetts, USA,
15
Foundation for Burkitt Lymphoma Research,
Geneva, Switzerland,
16
National Cancer Institute, National Institutes of
Health, Laboratory of Pathology, Clinical Center, Bethesda, Maryland,
USA,
17
Instituto Nacional de Cancer Jose de Alencar, Programa de
Oncovirologia, Rio de Janeiro, Brazil,
18
National Cancer Institute,
Figure 1A: Overall survivalCOO by Hans method Figure 1B: Overall survivalCOO by Nanostring Figure 1C: Overall survival
DHL and nonDHL Figure 1D: Overall survivalDEL and nonDEL
SUPPLEMENT ABSTRACTS
-
113
National Institutes of Health, Division of Cancer Epidemiology and
Genetics, Rockville, Maryland, USA,
19
St. Jude Children's Research
Hospital, Department of Pathology, Memphis, Tennessee, USA,
20
Canada's Michael Smith Genome Sciences Centre at BC Cancer,
Vancouver, Canada,
21
Uganda Cancer Institute, Kampala, Uganda,
22
Memorial Sloan Kettering Cancer Center and Weill Cornell Medical
College, New York, New York, USA,
23
St. Mary's Hospital Lacor,
EMBLEM Study, Gulu, Uganda,
24
National Institute of Allergy and
Infectious Diseases, National Institutes of Health, Division of Intramural
Research, Bethesda, Maryland, USA,
25
University of Pittsburgh School
of Medicine Presbyterian, Division of Hematopathology, Pittsburgh,
Pennsylvania, USA,
26
Hôpital Lyon Sud, Hospices Civils de Lyon,
Université Lyon 1, Service d'Anatomie Pathologique, Lyon, France,
27
Center for Cancer Research, National Cancer Institute, Lymphoid
Malignancies Branch, Bethesda, Maryland, USA
Introduction: Burkitt lymphoma (BL) is an aggressive Bcell non
Hodgkin lymphoma that disproportionately affects populations in
malariaendemic regions. Although BL is curable, age is associated
with inferior clinical outcomes in most series, but the genetic basis of
response is unknown. Recent large efforts in the characterization of
pediatric BL (pBL) showed key genomic aberrations underlying dis-
ease progression. However, these studies have not focused on
structural abnormalities of a large number of adult BL (aBL). In this
study, we aimed to identify agespecific genomic landscapes of copy
number variations (CNV) in BL.
Methods: Two cohorts comprising 124 pBL and 89 aBL patients,
representing both EBVpositive and EBVnegative cases within BL
Genomic Sequencing Project, were used in the study. Age cutoff
between pBL and aBL was 20 years. In addition, genomes from 186
patients with diffuse large Bcell lymphomas (DLBCL) were included
in our analysis for comparison. Somatic CNV were detected using
Battenberg and ControlFREEC algorithms.
Results: In BL, the proportion of genome altered by CNV was
significantly lower when compared with DLBCL. This difference can
be attributed to the higher average length of CNV (P<0.0001) and
frequency of wholegenome duplication (P<0.0001) in DLBCL. In
aBL specifically, amplifications within long arms of chromosomes 7,
10, 11, 15, 16, 19, and 20, or deletions affecting the short arm of
chromosome 9 were found at a higher frequency compared to pBL.
The amplified regions uniquely altered among aBL included genes
involved in the regulation of MYC function, such as KAT5, COPS6,
TRRAP, and PRMT1, suggesting they contribute to the MYC tran-
scriptional program. Importantly, aberrations within aBLspecific re-
gions showed no difference when stratified on EBV status or patient
sex. In contrast, when patients are stratified based on EBV status,
EBVnegative BL samples are uniquely associated with recurrent
amplifications within long arms on chromosomes 1 and 13, as well as
deletions at 6q15 and 11q25. The recurrent CNVs specific to EBV
negative BL are resulting in deletion of PRDM1 (identified in 6.9%
EBVnegative aBL and not detected in EBVpositive aBL) and
amplification of the locus containing FCGR2B (found in 24.1% EBV
negative aBL and not identified in EBVpositive aBL), a known
contributor to rituximab resistance in DLBCL and chronic lympho-
cytic leukemia.
Conclusions: We show that aBL has a distinct CNV profile
compared to pBL, suggesting either distinct mutational processes or
selective pressures in this malignancy. These differences are not
explained when samples are stratified on EBV status or sex. aBL
specific CNVs affect genes that regulate or cooperate with MYC
mediated transactivation. In addition, we show that chromosomal
abnormalities affecting 1q, 6q, and 13q predominantly occur in
EBVnegative BL.
Keywords: Genomics, Epigenomics, and Other Omics, Tumor Biology
and Heterogeneity, Aggressive Bcell nonHodgkin lymphoma
No conflicts of interests pertinent to the abstract.
068 |KEY GENETIC AND MOLECULAR ABERRATIONS
IDENTIFIED IN BOTH ADULT AND EBVPOSITIVE BURKITT
LYMPHOMA PATIENTS
J. Orem
1
, M.R. Martin
2
, S. M. Mbulaiteye
3
, C. G. Mullighan
4
,
A. J. Mungall
5
, K. Mungall
5
, C. Namirembe
1
, A. Noy
6
, H. Petrello
7
,
M. D. Ogwang
8
, J.P. Martin
2
, S. J. Reynolds
9
, S. H. Swerdlow
10
,
A. TraverseGlehen
11
, W. H. Wilson
12
, M. A. Marra
5
, L. M. Staudt
13
,
D. W. Scott
14
, R. D. Morin
15
, G. Timothy
16
, M. Dryer
17
, K. Dreval
15
,
D. S. Gerhard
18
, L. K. Hilton
14
, J. S. Abramson
19
, N. L. Bartlett
20
,
J. Bethony
21
, J. Bowen
7
, A. Bryan
7
, C. Casper
22
, N. Thomas
15
,
J. M. GastierFoster
23
, B. M Grande
24
, N. B. Griner
18
, T. G. Gross
25
,
N. L. Harris
26
, J. D. Irvin
2
, E. Jaffe
27
, F. Leal
28
1
Uganda Cancer Institute, Kampala, Uganda,
2
Foundation for Burkitt
Lymphoma Research, Geneva, Switzerland,
3
National Cancer Institute,
National Institutes of Health, Division of Cancer Epidemiology and
Genetics, Rockville, USA,
4
St. Jude Children's Research Hospital,
Department of Pathology, Memphis, USA,
5
BC Cancer, Canada's
Michael Smith Genome Sciences Centre, Vancouver, Canada,
6
Memorial
Sloan Kettering Cancer Center and Weill Cornell Medical College, New
York, USA,
7
Nationwide Children's Hospital, Pathology, Columbus, USA,
8
St. Mary's Hospital Lacor, EMBLEM Study, Gulu, Uganda,
9
National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, Division of Intramural Research, Bethesda, USA,
10
University of
Pittsburgh School of Medicine Presbyterian, Division of
Hematopathology, Pittsburgh, USA,
11
Hôpital Lyon Sud, Hospices Civils
de Lyon, Université Lyon 1, Service d'Anatomie Pathologique, Lyon,
France,
12
Center for Cancer Research, National Cancer Institute,
Lymphoid Malignancies Branch, Bethesda, USA,
13
Center for Cancer
Research, National Cancer Institute, Lymphoid Malignancies Branch,
Bethesda, USA,
14
BC Cancer, Centre for Lymphoid Cancer, Vancouver,
Canada,
15
SFU, Molecular Biology and Biochemistry, Burnaby, Canada,
16
University of Nebraska Medical Center, Department of Pathology and
Microbiology, Omaha, USA,
17
Frederick National Laboratory for Cancer
Research sponsored by the National Cancer Institute, Clinical Research
Directorate, Frederick, USA,
18
National Cancer Institute, National
Institutes of Health, Office of Cancer Genomics, Bethesda, USA,
114
-
SUPPLEMENT ABSTRACTS
19
Harvard Medical School, Center for Lymphoma, Massachusetts
General Hospital, Boston, USA,
20
Washington University, School of
Medicine, St. Louis, USA,
21
George Washington University, Department
of Microbiology, Immunology, and Tropical Medicine, Washington, USA,
22
Infectious Disease Research Institute, Infectious Disease Research
Institute, Seattle, USA,
23
The Ohio State University, Departments of
Pathology and Pediatrics, Columbus, USA,
24
Sage Bionetworks, Seattle,
USA,
25
National Cancer Institute, National Institutes of Health, Center
for Global Health, Rockville, USA,
26
Massachusetts General Hospital,
Harvard Medical School, Department of Pathology, Boston, USA,
SUPPLEMENT ABSTRACTS
-
115
27
Clinical Center, National Cancer Institute, National Institutes of
Health, Laboratory of Pathology, Bethesda, USA,
28
Instituto Nacional
de Cancer Jose de Alencar, Programa de Oncovirologia, Rio de Janeiro,
Brazil
Introduction: Burkitt lymphoma (BL) is the most common Bcell
nonHodgkin lymphoma (NHL) in children accounting for 50%
of pediatric NHLs, while accounting for only 12% of adult NHLs.
The genetic hallmark of BL is a translocation that places MYC
under the regulation of an immunoglobulin (IG) heavy or light
chain enhancer. Recently, we described molecular differences be-
tween EBVpositive (EBV+) and EBVnegative (EBV) pediatric
BLs. Specifically, EBV +BLs are characterized by elevated
expression of activationinduced cytidine deaminase, higher
genomewide mutation burden due to aberrant somatic hyper-
mutation, and fewer driver mutations per tumor. The limited
available studies comparing pediatric BL (pBL) to adult BL (aBL)
have revealed the latter more frequently harbor MYCIG light
chain rearrangements and possibly display some distinct driver
mutation profiles. The inferior survival rates of aBL patients ne-
cessitates the need for a better understanding of the full suite of
genetic and molecular features of aBL to enable more effective
treatments and prognostication within this population. Further,
important differences that distinguish EBV +BL tumors from
EBVtumors have only recently been elucidated and the multi
faceted role EBV plays in BL pathogenesis remains incompletely
understood.
Methods: We performed whole genome sequencing and RNAseq on
205 BL tumors: 124(91 EBV+) pBL and 81(26 EBV+) aBL cases. We
analyzed mutation patterns to identify significantly mutated genes
(SMGs) and compared their frequencies between EBV+/BL and
aBL/pBL.
Results: We identified 4 SMGs not previously associated with BL:
TET2, HNRNPU, BRAF, and EZH2. Three of these are commonly
mutated in other cancers and at variable rates in diffuse large B
cell lymphoma. We specifically associate TET2 mutations with aBL
versus pBL (11% vs 1.6%, Q =0. 0.09)(Fig. 1A). TP53 mutations
were associated with significantly inferior progression free survival
(PFS) in aBL at 2yr follow up (Fig. 1B). HNRNPU mutations have
not previously been linked to any cancer. These were mostly
truncating variants that track with EBVpositivity (Fig. 1A), with
mutant cases having significantly reduced expression of HNRNPU
mRNA.
Conclusion: This work highlights key mechanisms underlying BL
pathogenesis and key genetic differences based on age and EBV
status. We show the first evidence of mutations in TET2, HNRNPU,
BRAF, and EZH2 being associated with BL, with TET2 mutations
specifically associated with aBL. Among the SMGs, TP53 mutations
were associated with inferior PFS in aBL, presenting a subset of
patients to be considered for novel treatment approaches. These
findings further elucidate differences between adult and pediatric
BL and highlight model systems for the further development of
novel therapeutics exploiting these differences.
The research was funded by: Burkitt Lymphoma Research, National
Cancer Institute and Canadian Institutes of Health Research
Keywords: NonHodgkin (Pediatric, Adolescent, and Young
Adult)
No conflicts of interests pertinent to the abstract.
069 |TRIPLE POSITIVE (CD10 +BCL6 +MUM1+) DIFFUSE
LARGE BCELL LYMPHOMAS IN ADULTS ARE A
HETEROGENEOUS GROUP ENRICHED IN LARGE BCELL
LYMPHOMAS WITH IRF4 REARRANGEMENT
L. Frauenfeld
1
, N. CastrejondeAnta
2
, J. E. RamisZaldivar
3
, F. Otto
1
,
S. Streich
1
, J. SalmerónVillalobos
3
, A. Mayer
1
, J. Steinhilber
1
,
M. Pinyol
2
, B. Mankel
1
, I. Bonzheim
1
, F. Fend
1
, L. Rimza
4
,
I. Salaverria
3
, E. Campo
2
, O. Balagué
2
, L. QuintanillaMartinez
1
1
University of Tübingen, Institute for Pathology, Tübingen, Germany,
2
Hospital Clínic de Barcelona, Hematopathology Unit, Barcelona, Spain,
3
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS),
Centro de Investigación Biomédica en Red de Cáncer (CIBERONC),
Barcelona, Spain,
4
Mayo Clinic, Division of Hematopathology, Phoenix,
AZ, USA
Introduction: Gene expression profiling (GEP) divides DLBCL ac-
cording to the cell of origin (COO) into GCB, ABC and unclassifiable
(UNC), exhibiting different mutational profiles. The Hans algorithm
(HA), a surrogate of GEP, classifies cases expressing CD10, BCL6 and
MUM1 as GCB but it is not clear whether all these cases correspond
to GCBtype. Accordingly, LBCL with IRF4 rearrangement (LBCL
IRF4) usually expresses a GCB phenotype (CD10+, BCL6+) together
with strong MUM1/IRF4. The aim of this study was to characterize
the molecular heterogeneity of DLBCL triple positive (CD10 +BCL6
+MUM1+) in adults.
Methods: Fiftyfive triple positive DLBCL were investigated with
FISH (BCL2, BCL6, MYC, IRF4, IGH, IGL), NGS targeted sequencing
(SureSelectXT, 66 genes), COO using Nanostring and/or HTG mo-
lecular, and copy number (CN) analysis using Oncoscan platform. The
mutational subtype was defined using the algorithm by Wright et al
(Cancer Cell 2020).
Results: According to GEP, 32/54 (59%) cases were classified as
GCB, 17/54 cases (32%) as ABC, and 5/54 (9%) UNC. Based on
FISH analyses 3 groups were recognized. Group 1 included 15/55
cases (27%) without translocations. Eight cases (54%) were GCB,
whereas 7 cases ABCtype (46%). The MCD mutational profile
predominated in this group (6/12; 50%). Group 2 included 11/55
cases (20%) with isolated IRF4 alterations; 5 cases each were sub
classified either as GCB or ABC. This group was characterized by
one or multiple IRF4 mutations (82%) and frequent MYD88,
116
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SUPPLEMENT ABSTRACTS
CARD11 and CD79B mutations. In two cases no IRF4 break was
identified; however, these two cases had a light chain IG break and
multiple IRF4 mutations. Group 3 included 29/55 cases (53%) with
one or several translocations in BCL2/BCL6/MYC/IGH. Two of these
cases had a complex FISH constellation with BCL2 and/or BCL6
together with IRF4 translocation. In this group predominated the
GCBtype (19/29; 66%) and the EZB (8/25; 32%) mutational pro-
file. Oncoscan was performed in 7 cases of LBCLIRF4. A total of
118 genetic alterations were identified (mean: 17 CNA/case). The
comparison between LBCLIRF4 in adults and previously published
data in pediatric population (figure) showed no difference in terms
of recurrent CN regions; however, adult cases showed higher ge-
netic complexity (17 vs 6.25 alt/case; P =0.33) and more often
ABC COO (P =0.05). Mutational comparison showed higher
mutational load in adult cases (10.6 vs 4.7 mutation/case; P =
0.004) and higher frequency of KMT2D, MYD88 and BTG2 muta-
tions (P <0.05).
Conclusion: 1) Triple positive DLBCL is a heterogeneous group that
should not be classified with the HA. 2) Triple positive DLBCL in
adults are enriched in LBCLIRF4 (20%) and show frequent IRF4
mutations, which are absent in other groups. 3) LBCLIRF4 in adults is
more often ABCtype and shows higher genetic complexity when
compared with the pediatric counterpart.
Keywords: Pathology and Classification of Lymphomas
No conflicts of interests pertinent to the abstract.
SESSION 11: HODGKIN LYMPHOMA
070 |CIRCULATING TUMOR DNA IS A PROGNOSTIC
BIOMARKER IN CLASSIC HODGKIN LYMPHOMA
V. Spina
1
, M. C. Pirosa
2
, A. Bruscaggin
1
, A. Condoluci
1
, K. Pini
1
,
G. Forestieri
1
, I. Zangrilli
3
, M. di Trani
4
, M. Kurlapski
5
, A. Moccia
6
,
R. Moia
7
, P. Bulian
8
, S. Annunziata
9
, E. Borsatti
10
, M. Rodari
11
,
G. Romanowicz
12
, G. M. Sacchetti
13
, M. Faderl
1
, R. Koch
1
,
D. Piffaretti
1
, L. Terzi di Bergamo
1
, A. Stasia
2
, M. Cittone
2
,
SUPPLEMENT ABSTRACTS
-
117
S. Chauvie
14
, G. Stüssi
2
, B. Gerber
2
, A. Stathis
6
, S. Gillessen
Sommer
6
, F. Cavalli
1
, E. Zucca
6
, V. Gattei
8
, J. M. Zaucha
5
,
A. Pinto
15
, G. Gaidano
7
, C. CarloStella
4
, S. Hohaus
3
, L. Ceriani
16
,
D. Rossi
1
1
Institute of Oncology Research, Division of Experimental Hematology,
Bellinzona, Switzerland,
2
Oncology Institute of Southern Switzerland,
Division of Hematology, Bellinzona, Switzerland,
3
Fondazione Policlinico
Universitario Agostino Gemelli IRCCS, Department of diagnostic imaging,
oncological radiotherapy and hematology, Rome, Italy,
4
Humanitas
Clinical and Research Center, Humanitas Cancer Center, Milan, Italy,
5
Medical University of Gdańsk, Department of Hematology and
Transplantology, Gdańsk, Poland,
6
Oncology Institute of Southern
Switzerland, Clinic of Medical Oncology, Bellinzona, Switzerland,
7
University of Eastern Piedmont, Division of hematology, Novara, Italy,
8
Centro di Riferimento Oncologico di Aviano (CRO) IRCCS, Clinical and
Experimental OncoHematology Unit, Aviano, Italy,
9
Università Cattolica
del Sacro Cuore, Institute of Nuclear Medicine, Rome, Italy,
10
IRCCS CRO,
Nuclear Medicine, Aviano, Italy,
11
Humanitas Clinical and Research
Center, IRCCS, Unit of Nuclear Medicine, Milan, Italy,
12
Medical Univer-
sity of Gdansk, Department of Nuclear Medicine, Gdansk, Poland,
13
“Maggiore della Carità” Hospital, Nuclear Medicine, Novara, Italy,
14
Santa Croce e Carle Hospital, Department of Medical Physics, Cuneo,
Italy,
15
National Cancer Institute, Fondazione “G. Pascale” IRCCS,
HematologyOncology and Stem Cell transplantation Unit, Naples, Italy,
16
Imaging Institute of Southern Switzerland, Clinic of Nuclear Medicine
and Molecular Imaging, Bellinzona, Switzerland
Introduction: Current prognostic models of classic Hodgkin lym-
phoma (cHL) incorporate pretreatment clinical and laboratory
parameters, but have low discrimination capacity and limited clinical
utility. Circulating tumor DNA (ctDNA) is a sensitive cancer
biomarker, but its clinical validity in cHL is unknown. Here we tested
whether pretreatment ctDNA qualification and quantification is
prognostic in cHL.
Methods: The IOSIEMA003 (NCT03280394) is a prospective,
observational, multicentric, international, noninterventional trial in
which liquid biopsy samples were collected from newly diagnosed
cHL patients at the following time points: baseline, interim and end of
treatment PET/CT assessments. The LyV4.0 ctDNA CAPPseq assay
(sensitivity: 0.1%) was used to qualify and quantify ctDNA. Clinical
data quality was assured through remote medical monitoring. Base-
line, interim and end of treatment PET/CT are undergoing central
review.
Results: A total of 135 patients were recruited. Baseline charac-
teristics were those expected in unelected, previously untreated
cHL. After a median followup of 33 months, 25 patients had
progression events, accounting for 3year progression free survival
(PFS) of 80.0%. At baseline, ctDNA was detected in 90% of pa-
tients, with an average of 27 somatic mutation reporters per case.
A summary of genes affected by nonsynonymous, synonymous, and
noncoding somatic mutations is shown in Figure A. Median ctDNA
load was 358.5 hGE/mL of plasma (range 016572.4), and corre-
lated (p =0.004) with clinical proxies of the tumor volume (Figure
B). None of the genes mutated in 5% of patients, including TP53,
stratified PFS (Figure C). By recursive partitioning, ctDNA load in
baseline samples stratified PFS with an optimized threshold of
1500 hGE/mL of plasma (Figure D). Patients with high pre
treatment levels of ctDNA had significantly inferior rates of 3
118
-
SUPPLEMENT ABSTRACTS
year PFS (44.4% vs 86.9% p =0.000006) than those with low
levels (Figure E). High pretreatment levels of ctDNA occurred: i)
in 0% of early, 12.2% of intermediate and 15.9% of advanced cHL;
and ii) in 6.0% of 02 international prognostic score (IPS) and
27.3% of >3 IPS cHL. Levels of pretreatment ctDNA marked
patients’ outcome, irrespective of whether they presented in in-
termediate or advanced stage. The combination of high pre
treatment ctDNA and poor IPS risk >3 allowed to sort out
upfront poor risk cHL showing a 3year PFS of only 33.3% (Figure
F). In multivariable analysis, the interaction between pretreatment
ctDNA and IPS remained prognostic for PFS (HR 7.3, 95% CI 3.0
17.5, p =0.00009) when controlling for GHSG risk. PFS prediction
metrics (cindex) were 64.9% for ctDNA, 66.2% for IPS and 69.8%
for IPS combined to ctDNA.
Conclusions: ctDNA load is a strong, independent prognostic factor
in cHL. Next studies should aim at the external validation of this
biomarker and to its integration with radiomics.
The research was funded by: Fond’Action, Lausanne, Switzerland;
Translational Research Program, No. 659420, The Leukemia &
Lymphoma Society, New York
Keywords: Diagnostic and Prognostic Biomarkers, Hodgkin
lymphoma
Conflicts of interests pertinent to the abstract
A. Moccia
Consultant or advisory role: Roche, Janssen and Takeda
D. Rossi
Honoraria: AbbVie, AstraZeneca, Janssen
Research funding: AbbVie, AstraZeneca, Janssen.
071 |RELAPSES IN INTERIM PET NEGATIVE LIMITED STAGE
HODGKIN LYMPHOMA PATIENTS RECEIVING ABVD WITH OR
WITHOUT RADIOTHERAPY–ANALYSIS OF EORTC/FIL/LYSA H10
AND UK NCRI RAPID TRIALS
I. Aurer
1
, A. Neven
2
, V. Fiaccadori
3
, N. Counsell
4
, E. Phillips
5
,
L. CliftonHadley
4
, C. Fortpied
2
, M. Andre
6
, M. Federico
7
,
S. Barrington
8
, T. Illidge
5
, J. Radford
5
, J. Raemaekers
9
1
University Hospital Centre Zagreb, Division of Hematology, Department
of Internal Medicine, Zagreb, Croatia,
2
European Organisation for
Research and Treatment of Cancer, Lymphoma Group, Brussels, Belgium,
3
University College London, Cancer Institute, London, UK,
4
University
College London, Cancer Research UK and University College London
Cancer Trials Centre, London, UK,
5
University of Manchester, The Christie
NHS Foundation Trust and NIHR Manchester Biomedical Research
Centre, Manchester, UK,
6
Université Catholique de Louvain, Department
of Hematology, Yvoir, Belgium,
7
University of Modena and Reggio Emilia,
CHIMOMO Department, Modena, Italy,
8
King's College London, King's
College London and Guy's and St Thomas' PET Centre, London, UK,
9
Radboud University Medical Centre, Department of Hematology,
Nijmegen, Netherlands
Introduction: Randomized trials H10 and RAPID were designed to
assess whether radiotherapy (RT) can be safely omitted in newly
diagnosed limitedstage Hodgkin lymphoma (HL) patients who are
interim PETnegative (iPETneg) after 2 (H10) or 3 (RAPID) cycles of
ABVD. Despite differences in inclusion criteria and treatment, in both
studies relapses were more frequent after chemotherapy only (C)
than after combined modality treatment (C+RT), even in iPETneg
patients. A recent exploratory analysis of the H10 study showed that
most relapses after C occurred in the first 2 years after treatment
(early relapses) and were observed in initially involved areas. Male
sex and stage II were negative prognostic factors in H10. We sought
to confirm these findings in the independent data set of the RAPID
trial.
Patients and Methods: Patients enrolled in the RAPID trial were
assigned retrospectively to a favorable (F) or unfavorable (U) prog-
nostic group according to the EORTC/GELA criteria. First, the timing
and site of relapses were analyzed descriptively in the F group. The
low number of relapses in the U group prevented a reliable com-
parison with the H10 counterpart. Next, RAPID (F+U groups) was
analyzed with a Cox model adjusted for age, sex and stage to esti-
mate the treatment hazard ratio (HR) and its 95% confidence interval
(CI). Finally, H10 and RAPID (F+U groups) were combined in a Cox
model stratified by study, with a different HR before and after 2
years.
Results: Patient numbers, group allocation and outcomes are pre-
sented in table 1. In the RAPID F group, relapses after C occurred
within 2 years in 11 patients and after that in 2; and after C+RT in 2
and 4 patients, respectively. Relapses after C occurred only in initially
involved areas in 6 patients, only in uninvolved areas in 2 and in both
in 5; and after C+RT, in 1, 2 and 3 patients, respectively. In RAPID (F
+U groups), the effect of gender and stage went in the same direction
as in H10 but was nonsignificant. In the combined analysis, the
hazard of relapses was significantly lower after C+RT than after C
during the first 2 years (HR =0.20, 95% CI =(0.11, 0.37)) but similar
from 2 years onwards (HR =0.84, 95%CI =(0.41, 1.69)). The fitted
model showed a significant prognostic effect of gender (worse
prognosis for males) and stage (worse prognosis for stage II), mainly
driven by H10.
Conclusions: The independent validation with RAPID and the com-
bined analysis confirm the H10 finding that omitting RT in iPET neg.
patients treated with C results in an increase in early relapses.
Moreover, in both studies, relapses after C were more frequently
confined to initially involved areas alone.
Keywords: Hodgkin lymphoma, Radiation Therapy
No conflicts of interests pertinent to the abstract.
SUPPLEMENT ABSTRACTS
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119
072 |CALGB 50801 (ALLIANCE): PET ADAPTED
THERAPY IN BULKY STAGE I/II CLASSIC HODGKIN
LYMPHOMA (CHL)
A. S. LaCasce
1
, T. Dockter
2
, A. Ruppert
3
, L. Kostakoglu
4
, H. Schöder
5
,
E. D. Hsi
6
, J. A. Bogart
7
, B. D. Cheson
8
, N. D. WagnerJohnston
9
,
J. S. Abramson
10
, K. J. Maddocks
11
, J. P. Leonard
12
, N. L. Bartlett
13
1
Dana Farber Cancer Institute, Medical Oncology, Boston, USA,
2
Alliance Statistics and Data Center, Mayo Clinic, Rochester, USA,
3
Alliance Statistics and Data Center, The Ohio State University,
Columbus, USA,
4
University of Virginia, Radiology and Medical Imaging,
Charlottesville, USA,
5
Memorial Sloan Kettering Cancer Institute,
Molecular Imaging and Therapy Service, New York, USA,
6
Wake Forest
University Health Science, Pathology, WinstonSalem, USA,
7
SUNY
Upstate Medical University, Radiation Oncology, Syracuse, USA,
8
Lym-
phoma Research Foundation, Scientific Advisory Board Member, New
York, USA,
9
The Sidney Kimmel Comprehensive Cancer Center at Johns
Hopkins, Oncology, Baltimore, USA,
10
Massachusetts General Hospital
Cancer Center, Hematology/Oncology, Boston, USA,
11
Ohio State Uni-
versity Wexner Medical Center, Columbus, OH, Hematology, Columbus,
USA,
12
Meyer Cancer Center, Weill Cornell Medical College, Hematol-
ogy and Medical Oncology, New York, USA,
13
Washington University
School of Medicine in St. Louis and Siteman Cancer Center, Medical
Oncology, St. Louis, USA
Background: Bulky disease is associated with inferior outcomes in
patients with early stage cHL. Historically, most patients (pts)
receive chemotherapy followed by radiotherapy (RT), which is
associated with longterm toxicity. We tested a PETadapted
approach to reduce the need for RT in pts with early PET
negative (PET) disease and escalate therapy in pts with PET
positive (PET+) disease.
Methods: Eligible pts aged 1860 years (yrs) had stage IAIIB cHL
with disease bulk >10 cm or >.33 max intrathoracic diameter on
chest xray. Pts received 2 cycles of doxorubicinbleomycin
vinblastinedacarbazine (ABVD) followed by centrally reviewed
PET. PETwas defined as Deauville of 13. Pts who achieved a
negative PET scan (PET2) received 4 additional cycles of ABVD.
PET2+pts received 4 cycles of escBEACOPP plus 30 Gy involved
site radiation therapy. The primary endpoint was progressionfree
survival (PFS) estimated from PET2. With 93 pts and assuming
30% PET2+, there was 80% power to rule out that PFS of PET2+
pts was substantially inferior to PFS of PET2pts (HR 4.1, 3yr
PFS 40% vs 80%) if the true PFS of PET2+pts was closer to
that of PET2pts (HR 2.29, 3yr PFS 60% vs 80%) with onesided
alpha =0.15. With few events and mature followup, we report
results 3 yrs after the last pt was enrolled.
Results: Between May 2010 and October 2017, 101 pts enrolled.
Excluding 6 ineligible pts (3 without baseline DLCO, 2 did not
meet definition of bulk, 1 stage IIIB) and 1 pt without PET2, 94
were evaluable. 78% of pts were PET2(73 PET2, 21 PET2+).
Median age was 30 yrs (range: 18 to 58) and 53.2% were female.
Distribution of stage was: 1A 7.4%, IB 2.1%, IIA 39.4%, IIB
51.1%; 61.9% PET2+pts had stage IIB disease. Therapy was
generally well tolerated. Grade >3 neutropenia occurred in 86%
of pts with 8% of PET2and 10% of PET2+with grade >3 febrile
neutropenia. 3yr PFS estimates were 93.1% (95% CI: 87.499.1%)
in PET2pts, 89.7% (95% CI: 77.2100.0%) in PET2+pts (HR =
1.01, 85% upper bound 2.32), and 92.3% (95% CI: 87.098.0%) for
all pts. The protocoldefined primary endpoint was met as the PFS
hazard ratio for PET2+vs PET2was less than 4.1 (one sided p =
0.04). With a median followup of 5.5 yrs, 3 PET2pts died (HL,
anaplastic astrocytoma and COPD) and 1 PET2+died of pro-
gressive disease. 3yr overall survival (not a primary or secondary
outcome of the study) estimates were 98.6% (95% CI: 95.9
100.0%) in PET2pts, 94.4% (95% CI: 85.4100.0%) in PET2+pts
(HR: 1.2, 95% CI: 0.12, 11.60), and 97.7% (95% CI: 94.7100.0%)
for all pts.
Conclusions: Excellent PFS outcomes were observed in all pts using a
PETadapted approach that allowed omission of RT in 78% of pts. In
addition, PET2+pts treated with escalation to BEACOPP and con-
solidative RT did not have inferior outcomes.
EA previously submitted to ASCO 2021
The research was funded by: Support: U10CA180821,
U10CA180882; https://acknowledgments.alliancefound.org
Keywords: Hodgkin lymphoma
No conflicts of interests pertinent to the abstract.
TABLE 1Number, group allocation
and outcome of patients randomized in
the H10 and RAPID trials
F U Unclassified*
C+RT C C+RT C C+RT C
H10 randomized 227 238 292 302 0 0
relapsed 2 (1%) 30 (13%) 16 (5%) 30 (10%) 0 0
RAPID randomized 118 123 65 63 25 25
relapsed 6 (5%) 13 (11%) 3 (5%) 5 (8%) 0 3 (12%)
*
mainly due to missing ESR.
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SUPPLEMENT ABSTRACTS
073 |NEW PROGNOSTIC SCORE INCORPORATING MTV
PREDICTS TREATMENT FAILURE IN ADVANCED HODGKIN
LYMPHOMA
S. F. Barrington
1
, A. A. Kirkwood
2
, L. C. Pike
3
, C. Guezennec
4
, H. Li
5
,
M. le Blanc
6
, D. Poon
7
, M. V. Knopp
8
, L. CliftonHadley
9
, C. Lau-
bach
10
, H. Schöder
11
, J. W. Friedberg
12
, P. W. Johnson
13
1
Kings College London and Guy's and St Thomas' PET Centre, School of
Biomedical Engineering and Imaging Sciences, King's College London,
King's Health Partners, London, UK,
2
University College London, Cancer
Research UK and University College London Cancer Trials Centre,
London, UK,
3
Kings College London, Kings College London and Guy's
and St Thomas' PET Centre, London, UK,
4
Kings College London, Kings
College London and Guy's and St Thomas' PET Centre, London, UK,
5
Fred Hutchinson Cancer Research Center, SWOG Statistics and
Data Management Center, Seattle, USA,
6
Fred Hutchinson Cancer
Research Center, SWOG Statistics and Data Management Center,
Seattle, USA,
7
Ohio State University, IROC Ohio, Wright Center of
Innovation, Columbus, USA,
8
Ohio State University, IROC Ohio, Wright
Center of Innovation, Columbus, USA,
9
University College London,
Cancer Research UK and University College London Cancer Trials
Centre, London, UK,
10
SWOG Cancer Research Network, Operations
Office, San Antonio, Texas, USA,
11
Memorial Sloan Kettering
Cancer Center, Department of Radiology, New York, USA,
12
University
of Rochester, JWF Wilmot Cancer Institute, Rochester, USA,
13
University of Southampton, Department of Medical Oncology,
Southampton, UK
Background: The risk of treatment failure in Hodgkin lymphoma (HL)
might be assessed more accurately by incorporating presentation
features such as disease severity using FDGPET characteristics to
guide the intensity of initial therapy.
Methods: Twentyfour baseline clinical and PET factors were
evaluated in the UK RATHL
1
population including metabolic
tumour volume (MTV), tumor lesion glycolysis and SUV metrics.
The association of factors with the risk of a HL event, defined as a
positive interim PET scan at cycle 2 of ABVD, or relapse after a
negative interim scan, was explored using bootstrapping with Cox
regression and receiver operating characteristicarea under the
curve (ROCAUC) analysis (5year event) to derive a new prog-
nostic score. The score developed in a training set (n =521) was
tested in an internal validation set (n =261) and an independent
trial dataset of stage IIIIV HL pts (SWOG S0816
2
, n =333). MTV
using SUV4 was selected; Cox regression p 0.05 in 97.2% of
samples and highest ROCAUC in the majority of samples. Other
factors were included if they remained in a backwards selection
model in 50% of samples.
Results: The final model included MTV, lymphocytes as percentage of
total white cells and stage IV disease. Hazard ratio (HR) for a HL
event was 2.72 per unit increase in prognostic score (p <0.001), ROC
AUC: 0.65. The high risk group was chosen to be the 30% of pts with
the highest scores, considering various cut points in the training set
for acceptable risks for escalation of initial therapy.
HL 5year event rates were 22.1% and 45.4% for standard and
high risk pts respectively HR:2.40, p <0.001,(sensitivity 48%,
specificity 76.3%). 5year PFS for standard risk pts was 85.1%.
The new score discriminated better than IPS 02 vs 3+(sensi-
tivity 43.5%, specificity 68.1%), 22.6% pts would be incorrectly
deemed high risk using IPS compared to 17.5% with the new
score. For 1000 patients treated with ABVD by 5 years, 125/300
pts with a high risk score vs. 127/353 pts with IPS 3+would
have a HL event. Conversely 564/700 pts with a standard
risk score vs. 481/647 with IPS 02 would not experience a HL
event.
Combining the score with IPS provided no additional information
(Figure). The score validated in the internal and independent datasets
with results for stage III and IV pts from S0816 and RATHL (training
set) of: ROCAUC 0.62 and 0.61, sensitivity 57.1% and 55.5%,
specificity 57.6% and 60.7%, HR 1.66 (p =0.005) and 1.90 (p =
0.001); median follow up was 7 and 5.5 years for S0816 and RATHL
respectively.
Conclusion: This new prognostic score can be used to identify pts in
whom a more intensive initial therapy than ABVD would be most
useful, whilst avoiding escalation for those with a high chance of cure
with ABVD alone. As the score is continuous, the cut point could be
changed depending on the proposed therapy and the risk/reward
balance for over/under treatment.
1
N Engl J Med 2016;374:241929
2
Blood 2019;134:123846
The research was funded by: National Institute for Health Research
and Social Care RP21607001, Cancer Research UK (CRUK/07/
033)
Keywords: Diagnostic and Prognostic Biomarkers, PETCT, Hodgkin
lymphoma
Conflicts of interests pertinent to the abstract
A. A. Kirkwood
Research funding: Millennium pharmaceutics inc., BristolMyers
Squibb Pharmaceuticals Ltd., Amgen GmBbH., Celgene Ltd., Merck
Sharp and Dohme Ltd., JanssenCilag Ltd, Pfizer Ltd.
L. CliftonHadley
Research funding: Millennium pharmaceutics inc., BristolMyers
Squibb Pharmaceuticals Ltd., Amgen GmBbH., Celgene Ltd., Merck
Sharp and Dohme Ltd., JanssenCilag Ltd, Pfizer Ltd.
SUPPLEMENT ABSTRACTS
-
121
074 |NIVOLUMAB FOR RELAPSED OR REFRACTORY (R/R)
CLASSICAL HODGKIN LYMPHOMA (CHL) AFTER AUTOLOGOUS
TRANSPLANTATION: 5YEAR OVERALL SURVIVAL FROM THE
PHASE 2 CHECKMATE 205 STUDY
S. M. Ansell
1
, P. J. Bröckelmann
2
, G. von Keudell
3
, H. J. Lee
4
,
A. Santoro
5
, P. L. Zinzani
6
, G. P. Collins
7
, J. B. Cohen
8
, J. P. De Boer
9
,
J. Kuruvilla
10
, K. J. Savage
11
, M. Trneny
12
, M. Provencio
13
,
U. Jaeger
14
, W. Willenbacher
15
, R. Swanink
16
, M. Sacchi
17
,
M. A. Shipp
18
, A. Engert
19
, P. Armand
20
1
Mayo Clinic, Division of Hematology, Rochester, Minnesota, USA,
2
University Hospital of Cologne, Department of Internal Medicine,
Cologne, Germany,
3
Memorial Sloan Kettering Cancer Center,
Department of Hematology, New York, New York, USA,
4
University of
Texas MD Anderson Cancer Center, Department of Lymphoma and
Myeloma, Houston, Texas, USA,
5
Humanitas University, Humanitas
Cancer Center, Rozzano–Milan, Italy,
6
University of Bologna, Institute
of Hematology L. e A. Seràgnoli, Bologna, Italy,
7
Churchill Hospital,
Oxford Cancer and Haematology Centre, Oxford, UK,
8
Emory Univer-
sity, Winship Cancer Institute, Atlanta, Georgia, USA,
9
Antoni van
Leeuwenhoek Hospital, Netherlands Cancer Institute, Amsterdam,
Netherlands,
10
University of Toronto and Princess Margaret Cancer
Centre, Division of Medical Oncology and Hematology, Toronto, Can-
ada,
11
BC Cancer, Department of Medical Oncology, Vancouver, Can-
ada,
12
Charles University in Prague and General University Hospital in
Prague, Department of Haematology, Prague, Czech Republic,
13
Hos-
pital Universitario Puerta de Hierro, Department of Medical Oncology,
Madrid, Spain,
14
Medical University of Vienna, Clinical Department for
Hematology and Hemostaseology, Vienna, Austria,
15
Innsbruck Medical
University, Department of Internal Medicine V, Innsbruck, Austria,
16
Bristol Myers Squibb, Global Biometrics and Data Sciences, Braine
l’Alleud, Belgium,
17
Bristol Myers Squibb, Global Drug Development,
Princeton, New Jersey, USA,
18
DanaFarber Cancer Institute, Depart-
ment of Medical Oncology, Boston, Massachusetts, USA,
19
University
Hospital of Cologne, Department of Internal Medicine, Cologne, Ger-
many,
20
DanaFarber Cancer Institute, Department of Medical
Oncology, Boston, Massachusetts, USA
Introduction: PD1 immune checkpoint inhibitors, including the
monoclonal antibody nivolumab (NIVO), have shown strong activity
122
-
SUPPLEMENT ABSTRACTS
in patients (pts) with R/R cHL. The pivotal phase 2 CheckMate 205
study (NCT02181738) demonstrated an objective response rate
(ORR) of 69%, a median duration of response (DOR) of 17 mo, and
median progressionfree survival (PFS) of 15 mo in pts with R/R cHL
treated with NIVO after autologous hematopoietic cell trans-
plantation (autoHCT), with a median followup of 18 mo (Armand
et al. J Clin Oncol 2018). Recently, PD1 inhibitor monotherapy
showed significantly improved PFS vs brentuximab vedotin (BV) in R/
R cHL (Kuruvilla et al. ASCO 2020). However, longterm survival
benefit of anti–PD1 therapy and optimal duration of treatment (tx)
are unknown. We present updated results of CheckMate 205 with a
median followup of 58 mo.
SUPPLEMENT ABSTRACTS
-
123
Methods: CheckMate 205 enrolled pts with R/R cHL after autoHCT
failure into cohorts by tx history: BVnaive (cohort A), BV after auto
HCT (cohort B), and BV before and/or after autoHCT (cohort C). Pts
received NIVO 3 mg/kg every 2 wk until disease progression or un-
acceptable toxicity. Pts in cohort C discontinued nivo after 1 y in
complete remission (CR) and could resume if they relapsed within 2 y.
The primary endpoint was ORR per independent radiologic review
committee (IRRC); other endpoints included CR, DOR, PFS, overall
survival (OS), and safety.
Results: Overall, 243 pts were treated (63, 80, and 100 in cohorts A,
B, and C, respectively). Baseline characteristics were previously
described. Median duration of tx was 14 mo. ORR was 71% (95% CI,
65–77) with a CR rate of 21%. Median PFS was 15 mo (95% CI, 11–
19) and median DOR was 18 mo (95% CI, 15–26). Pts with CR had
longer median PFS (37 mo) and DOR (30 mo) than pts with partial
remission (PR; 15 and 13 mo, respectively). The 2y and 5y OS rates
(95% CI) were 87% (82–91) and 71% (65–77), and PFS rates were
37% (30–44) and 18% (12–25), respectively. Pts with CR also had
improved OS; failure to achieve disease control was a poor prog-
nostic factor for OS (Figure). Per protocol, 12 pts in cohort C stopped
study tx after 1 y of CR. At time of analysis, after a median of 48
mo (range 36–55) from last tx, 6 pts were still in response; 3 were re
treated with NIVO after disease progression (2 reachieved CR and 1
PR). No new toxicities were observed, and the most common tx
related adverse events (TRAEs) of any grade were fatigue (25%),
diarrhea (17%), and rash (12%), almost all grade 1–2. Grade 3–4
TRAEs occurred in 68 pts (28%). TRAEs led to discontinuation in
26 pts (11%). There were no txrelated deaths.
Conclusions: This 5y analysis of CheckMate 205 cohorts ABC
demonstrated a favorable OS and confirms the efficacy and safety of
NIVO for pts with cHL who progressed or relapsed after autoHCT.
The safety profile is similar to previous reports. It appears feasible to
stop NIVO after 1 y of CR and reinitiate tx upon disease progression.
The research was funded by: Bristol Myers Squibb
Keywords: Hodgkin lymphoma, Immunotherapy
Conflicts of interests pertinent to the abstract
S. M. Ansell
Research funding: Bristol Myers Squibb, Takeda, Seagen, AI Thera-
peutics, Regeneron, Trillium, Affimed, ADC Therapeutics
P. J. Bröckelmann
Consultant or advisory role Takeda
Honoraria: Bristol Myers Squibb, Takeda
Research funding: BeiGene, Bristol Myers Squibb, Merck Sharp &
Dohme, Takeda
Educational grants: Celgene
H. J. Lee
Consultant or advisory role Bristol Myers Squibb, Kite Pharma
Honoraria: Aptitude Health, Pharmacyclics, Cancer Experts, Guide-
point Global
Research funding: Bristol Myers Squibb/Celgene, Takeda, Seattle
Genetics, Janssen, Merck, Oncternal, Onyx
A. Santoro
Consultant or advisory role Bristol Myers Squibb, Servier, Gilead,
Pfizer, Eisai, Bayer, Merck Sharp & Dohme, Arqule, Sanofi
Other remuneration: Speaker's bureau: Takeda, Bristol Myers
Squibb, Roche, AbbVie, Amgen, Celgene, Servier, Gilead, AstraZe-
neca, Pfizer, Arqule, Lilly, Sandoz, Eisai, Novartis, Bayer, Merck
Sharp & Dohme
P. L. Zinzani
Consultant or advisory role Servier, Merck, Janssen, Eusapharma,
Takeda, Incyte, Gilead, Novartis
Honoraria: Servier, Merck, Janssen, Eusapharma, Takeda, Incyte,
Gilead, Novartis
G. P. Collins
Consultant or advisory role Bristol Myers Squibb, Merck Sharp &
Dohme, Gilead, Roche, Takeda, Incyte, Daiichi Sankyo, BeiGene,
Novartis, ADC Therapeutics
Honoraria: Bristol Myers Squibb, Merck Sharp & Dohme, Gilead,
Roche, Takeda, Incyte, Daiichi Sankyo, BeiGene, Novartis, ADC
Therapeutics
Research funding: Bristol Myers Squibb, Merck Sharp & Dohme,
Celleron, BeiGene, Amgen, Pfizer
J. B. Cohen
Consultant or advisory role BeiGene, Pharmacyclics, Adaptive, Apti-
tude Health, Gilead/Kite, Adicet, AstraZeneca
Research funding: Bristol Myers Squibb/Celgene, Novartis, Gen-
entech, Takeda, LAM, Loxo/Lilly, AstraZeneca, BeiGene
J. Kuruvilla
Consultant or advisory role Abbvie, Bristol Myers Squibb, Gilead,
Karyopharm, Merck, Roche, Seattle Genetics
Honoraria: Amgen, Antengene, AstraZeneca, Bristol Myers Squibb,
Gilead, Incyte, Janssen, Karyopharm, Merck, Novartis, Pfizer, Roche,
Seattle Genetics, TG Therapeutics
Research funding: Canadian Cancer Society, Leukemia and Lym-
phoma Society Canada, Princess Margaret Cancer Foundation,
Janssen, Roche, AstraZeneca
Other remuneration: Karyopharm (DSMB)
K. J. Savage
Consultant or advisory role Bristol Myers Squibb, Merck, Seattle
Genetics, Gilead, AstraZeneca, Novartis, Janssen, Kyowa, Servier
Other remuneration: Steering committee: BeiGene
M. Trneny
Consultant or advisory role Roche, Takeda, Bristol Myers Squibb,
Incyte, Abbvie, Amgen, Gilead Sciences, Janssen, MorphoSys, Novartis
Honoraria: Roche, Janssen, Gilead Sciences, Takeda, Bristol Myers
Squibb, Amgen, Abbvie, MorphoSys, Novartis
Educational grants: Gilead Sciences, Bristol Myers Squibb, Roche,
Janssen, Abbvie, Takeda
M. Provencio
Consultant or advisory role Bristol Myers Squibb, Merck Sharp &
Dohme, AstraZeneca, Takeda, Roche, Lilly
124
-
SUPPLEMENT ABSTRACTS
Research funding: Bristol Myers Squibb, Roche
U. Jaeger
Consultant or advisory role Bristol Myers Squibb, Celgene
Honoraria: Bristol Myers Squibb, Celgene
R. Swanink
Employment or leadership position: Bristol Myers Squibb
M. Sacchi
Employment or leadership position: Bristol Myers Squibb
M. A. Shipp
Consultant or advisory role Immunitas Therapeutics, AstraZeneca
Research funding: Bristol Myers Squibb, Merck, Bayer, AbbVie
A. Engert
Consultant or advisory role Takeda, ADC Therapeutics, Tessa
Pharmaceuticals
Honoraria: Bristol Myers Squibb, Takeda, Novartis, Merck Sharp &
Dohme, ONO Pharma, Hexal, AstraZeneca
Research funding: Bristol Myers Squibb, Takeda, Affimed
P. Armand
Consultant or advisory role Merck, Bristol Myers Squibb, Pfizer,
Affimed, Adaptive, ADC Therapeutics, Celgene, Morphosys, Daiichi
Sankyo, Miltenyi, Tessa, GenMab, C4, Enterome, Regeneron, Epi-
zyme, AstraZeneca, Genentech
Honoraria: Merck, Bristol Myers Squibb
Research funding: Merck, Bristol Myers Squibb, Affimed, Adaptive,
Genentech, IGM, Kite
075 |CAMIDANLUMAB TESIRINE EFFICACY AND SAFETY IN
AN OPENLABEL, MULTICENTER, PHASE 2 STUDY OF PATIENTS
(PTS) WITH RELAPSED OR REFRACTORY CLASSICAL HODGKIN
LYMPHOMA (R/R CHL)
P. L. Zinzani
1
, C. CarloStella
2
, M. Hamadani
3
, A. F. Herrera
4
,
S. M. Ansell
5
, J. Radford
6
, K. Maddocks
7
, J. Kline
8
, K. J. Savage
9
,
N. L. Bartlett
10
, P. F. Caimi
11
, Y. Negievich
12
, H. G. Cruz
12
, L. Wang
13
,
J. Wuerthner
12
, G. P. Collins
14
1
IRCCS Azienda OspedalieroUniversitaria di Bologna Istituto di Ema-
tologia “Seràgnoli”, and Dipartimento di Medicina Specialistica, Diag-
nostica e Sperimentale, Università di Bologna, Bologna, Italy,
2
Humanitas Clinical and Research Center IRCCS, and Humanitas
University, Department of Oncology and Hematology, Rozzano, Milan,
Italy,
3
Medical College of Wisconsin, BMT & Cellular Therapy Program,
Department of Medicine, Milwaukee, Wisconsin, USA,
4
City of Hope
Comprehensive Cancer Center, Department of Hematology & Hemato-
poietic Cell Transplantation, Duarte, California, USA,
5
Mayo Clinic,
Division of Hematology, Rochester, Minnesota, USA,
6
NIHR Manchester
Clinical Research Facility, The Christie NHS Foundation Trust and
University of Manchester, Manchester Academic Health Science Centre,
Manchester, UK,
7
Ohio State University Medical Center, Division of
Hematology, Columbus, Ohio, USA,
8
The University of Chicago,
Department of Medicine, Chicago, Illinois, USA,
9
BC Cancer and Uni-
versity of British Columbia, Department of Medical Oncology, Van-
couver, BC, Canada,
10
Washington University School of Medicine in St
Louis, Division of Oncology, St Louis, Montana, USA,
11
University
Hospitals Cleveland Medical Center/Case Western Reserve University,
Department of Medicine, Cleveland, Ohio, USA,
12
ADC Therapeutics SA,
Clinical Development, Epalinges, Switzerland,
13
ADC Therapeutics
America, Inc, Clinical Development, Murray Hill, New Jersey, USA,
14
Churchill Hospital, NIHR Oxford Biomedical Research Centre, Oxford
Cancer and Haematology Centre, Oxford, UK
Introduction: Camidanlumab tesirine (Cami) is an antibodydrug
conjugate comprising a human IgG1 antiCD25 monoclonal anti-
body conjugated to a pyrrolobenzodiazepine (PBD) dimer warhead.
Cami has demonstrated encouraging antitumor activity and
manageable toxicity in a Ph 1 trial in lymphomas, particularly R/R
cHL. Here we present preliminary results of a Ph 2 study of Cami
monotherapy in pts with R/R cHL.
Methods: Pts with R/R cHL and 3 prior therapy lines, including
brentuximab vedotin (BV) and PD1 blockade (2 lines if ineligible
for hematopoietic cell transplantation; HCT) were enrolled
(NCT04052997). An interim analysis was conducted after meeting a
protocolspecified criterion for pausing enrollment (Herrera et al.
Blood 2020;136:Suppl.1:21–3). After safety and efficacy review, the
pause was lifted. The primary objective is evaluation of Cami efficacy
by overall response rate (ORR; central review). Duration of response
(DOR) and progressionfree survival (PFS) are secondary efficacy
endpoints. Efficacy is reported for pts on study for 12 weeks since
first dose. Safety endpoints include frequency and severity of TEAEs,
assessed in all treated pts. Pts received Cami 45 μg/kg IV on Day 1 of
each 3week cycle for 2 cycles, then 30 μg/kg for subsequent cycles.
Results: As of Dec 4, 2020, 82 pts with R/R cHL had enrolled. Pts had
received a median of 7 (range 3–19) prior lines of therapy. Pts
received a mean (SD) of 4 (3.0) Cami cycles. Five of 47 (10.6%) pts
who discontinued treatment underwent HCT following Cami
administration.
In the 52 pts evaluable for efficacy, ORR was 82.7% (43/52 pts), with
38.5% (20/52) pts attaining complete response (Figure). Median DOR
was not reached at median (range) followup of 9.2 (2.0–14.3
[censored]) months. Median (95% CI) PFS was 9.2 (5.0–not reached)
months.
Allgrade TEAEs in 25% of 82 pts in the safety analysis set were
fatigue (34, 41.5%), nausea and maculopapular rash (each 23,
28.0%) and pyrexia (21, 25.6%). Grade 3 TEAEs in 5% pts were
hypophosphatemia (7, 8.5%) and lymphopenia (5, 6.1%). TEAEs
leading to Cami dose delay/reduction or discontinuation occurred
in 8 (9.8%) and 10 (12.2%) pts, respectively. Categories of TEAEs
considered PBDassociated included skin reactions/nail disorders
(48, 58.5%), liver function test abnormalities (23, 28.0%) and
SUPPLEMENT ABSTRACTS
-
125
edema/effusion (10, 12.2%). Guillain–Barré syndrome (GBS)/poly-
radiculopathy was reported in 4 (4.9%) pts: GBS in 2 pts (Grade 2,
resolved; Grade 4, improved); radiculopathy in 1 pt (Grade 2,
resolved); and encephalitis and polyneuropathy in 1 pt (Grade 3,
ongoing).
Conclusions: Cami demonstrated high ORR in heavily pretreated R/R
cHL after failure of BV and PD1 blockade, with encouraging DOR.
Data continue to mature. Safety remains consistent with prior find-
ings. Pt enrollment completed on Jan 29, 2021 and updated results
for the total population (N =117) will be presented.
The research was funded by: ADC Therapeutics SA
Keywords: Hodgkin lymphoma, Chemotherapy, Immunotherapy
Conflicts of interests pertinent to the abstract
P. L. Zinzani
Consultant or advisory role: Verastem, MSD, Eusapharma, and
Sanofi, ADC Therapeutics, Celltrion, Gilead, JanssenCilag, Bristol
Myers Squibb, Servier, Sandoz, TG Therapeutics, Takdea, Roche,
Eusapharma, and Kyowa Kirin
C. CarloStella
Consultant or advisory role: ADC Therapeutics, Roche, Sanofi, Kar-
yopharm Therapeutics, Celgene/BristolMyers Squibb, Incyte
Honoraria: BristolMyers Squibb, Merck Sharp & Dohme, Janssen
Oncology, AstraZeneca, Celgene, Takeda, Incyte, Gilead Sciences
Research funding: ADC Therapeutics
M. Hamadani
Consultant or advisory role: Consultancy services for Janssen
R&D, Incyte Corporation, ADC Therapeutics, Celgene Corporation,
Pharmacyclics, Omeros, AbGenomics, Verastem and TeneoBio;
speaker's bureau for Sanofi Genzyme, BeiGene and AstraZeneca
Research funding: Takeda Pharmaceutical Company, Spectrum
Pharmaceuticals and Astellas Pharma
A. F. Herrera
Consultant or advisory role: BristolMyers Squibb; Genentech/
Roche; Merck; Seattle Genetics; Karyopharm
Research funding: BristolMyers Squibb (Inst.); Genentech/Roche
(Inst.); Immune Design (Inst.); Merck (Inst.); Pharmacyclics (Inst.);
Seattle Genetics (Inst.)
Other remuneration: Travel/accommodation/expenses: Bristol
Myers Squibb
S. M. Ansell
Research funding: ADC Therapeutics, Bristol Myers Squibb, Seattle
Genetics, Affimed, Regeneron, Trillium, AI Therapeutics
J. Radford
Consultant or advisory role: Takeda, ADC Therapeutics, Bristol
Myers Squibb, Novartis and Kite Pharma; speaker for Takeda, ADC
Therapeutics and Seattle Genetics
Stock ownership: ADC Therapeutics and AstraZeneca (spouse)
Honoraria: Expert testimony for Takeda and ADC Therapeutics
Research funding: Takeda
K. Maddocks
Consultant or advisory role: ADC Therapeutics, AstraZeneca, BMS, Cel-
gene, Gilead, Karyopharm, Morphosys, Pharmacyclics, Seattle Genetics
Research funding: BMS
J. Kline
Consultant or advisory role: Merck, Kite/Gilead, Verastem, Mor-
phoSys, Karyopharm, Seagen
Research funding: Merck, Verastem, iTeos
K. J. Savage
Consultant or advisory role: Merck, BMS, Seattle Genetics, Gilead,
AstraZeneca, Novartis, Janssen, Kyowa, Servier
Honoraria: Merck, BMS, Seattle Genetics, Gilead, AstraZeneca,
Novartis, Janssen, Kyowa
FIGURE 1 Best overall responses in patients
with classical Hodgkin lymphoma (efficacy
analysis set
a
)
126
-
SUPPLEMENT ABSTRACTS
Research funding: Roche (Institutional)
Other remuneration: Beigene (Steering Committee)
N. L. Bartlett
Consultant or advisory role: ADC Therapeutics, Autolus, BristolMyers
Squibb, Celgene, Forty Seven, Immune Design, Janssen, Kite Pharma,
Merck, Millennium, Pfizer, Pharmacyclics, Roche/Genentech, Seattle
Genetics
Research funding: ADC Therapeutics
P. F. Caimi
Consultant or advisory role: Research support from ADC Therapeutics,
and Genentech; advisory boards for ADC Therapeutics, Genentech,
Kite Pharmaceuticals, Verastem, Seattle Genetics, and Amgen; con-
sultancy services for TG Therapeutics; speaker's bureau for Celgene
Y. Negievich
Employment or leadership position: ADC Therapeutics SA
Stock ownership: ADC Therapeutics SA
H. G. Cruz
Employment or leadership position: ADC Therapeutics SA
Stock ownership: ADC Therapeutics SA
L. Wang
Employment or leadership position: ADC Therapeutics America, Inc
Stock ownership: ADC Therapeutics America, Inc
J. Wuerthner
Employment or leadership position: ADC Therapeutics SA
Stock ownership: ADC Therapeutics SA
G. P. Collins
Consultant or advisory role: ADC Therapeutics, Roche, Takeda, BMS,
MSD, Celleron, Beigene, Gilead, Novartis, Daiichi Sankyo, Incyte and
Celgene
Research funding: Celgene, Amgen, MSD, BMS, and Celleron
SESSION 12: INDOLENT LYMPHOMAS
076 |INTRATUMORAL TCELLS HAVE A DIFFERENTIAL IMPACT
ON FDGPET PARAMETERS IN FOLLICULAR LYMPHOMA
K. Nath
1
, SoiC. Law
1
, D. Talaulikar
2
, M. B. Sabdia
1
, J. Gunawardana
1
,
L. M. de Long
1
, M. Shanavas
1
, H. Tsang
1
, J. W. Tobin
1
, S.J. Halliday
3
,
A. Hernandez
3
, D. Cross
3
, R. Bird
3
, S. Jain
4
, C. Keane
1
, J. Trotman
5
,
P. Law
6
, M. K. Gandhi
1
1
Mater Research Institute, University of Queensland, Brisbane, Australia,
2
Haematology Translational Research Unit, Canberra Hospital, Canberra,
Australia,
3
Princess Alexandra Hospital, Department of Haematology,
Brisbane, Australia,
4
Canberra Hospital, Department of Anatomical
Pathology, Canberra, Australia,
5
Concord Repatriation General Hospital,
Department of Haematology, Sydney, Australia,
6
Princess Alexandra
Hospital, Department of Medical Imaging, Brisbane, Australia
Introduction: Results of the prognostic impact of the pretherapy
FDGPET parameters TMTV (3D tumor burden of all involved sites)
and SUV
max
(highest FDGuptake within a single lesion) in follicular
lymphoma (FL) are conflicting and appear to vary between chemo-
immunotherapy regimens. Similarly, the predictive utility of pre
therapy Teffector genes is reversed between patients treated with
‘CHOP/CVP’R/O and those treated with BR/O (Bolen, Blood, 2021).
Notably, BR (unlike RCHOP) causes profound/sustained Tcell
depletion. The relationship between intratumoral Tcells and PET pa-
rameters is unknown.
Methods: A comprehensive molecular and functional analysis was
undertaken in 83 patients with denovo Grade IIIIa FL.
Results: Low intratumoral Tcell gene expression (by NanoString) was
associated with 6fold higher TMTV (41%SUV
max
and fixed SUV>2.5
thresholds) and 7fold higher TLG (total lesional glycolysis) (Fig 1A
B). Consistent with this, FL nodes with increased malignant Bcell
infiltration (by flow cytometry) showed high TMTV (Fig 1C). Since T
cell clonal infiltration of the tumor microenvironment (TME) is prog-
nostic in FL (Tobin, JCO, 2019), we reasoned that clonal expansions
within intratumoral Tcell compartments may reflect differential
TMTV. To test this, we FACS sorted Tcells from deaggregated nodes
into CD8
+
(activated, exhausted, resting) and CD4
+
(Tfollicular helper
[T
FH
], Tregulatory [T
REG
], nonT
FH
/T
REG
CD4
+
cells) intratumoral T
cell subsets. High TMTV patients had fewer clonally expanded acti-
vated CD8
+
and CD4
+
T
FH
cells (by TCR sequencing) than low TMTV
patients (Fig 1DE). Next, to directly compare glucoseuptake between
Band Tcells, a fluorescently labelled glucose analogue (2NBDG) flow
cytometry assay was performed. Glucoseuptake was higher in CD4
+
and CD8
+
Tcells than in intratumoral Bcells (Fig 1F). However, as
CD19
+
Bcells contributed 2/3
rds
of the total lymphocytes, they
contribute most to overall glucoseuptake (Fig 1G), demonstrating that
TMTV reflects the burden of the malignant population. To test SUV
max
,
we interrogated a unique subset of 12 patients in whom prebiopsy PET
scans were available. This allowed comparison of the TME gene
expression profile of the excised node with its corresponding prebiopsy
SUV
max:
(‘lesional SUV
max
’), thereby accounting for the impact of SUV
on tumor spatial heterogeneity. Lesional SUV
max
associated with CD4
and CD8A, but not CD19 (Fig 1H).
Conclusion: TMTV best reflects the malignant FL Bcell burden,
whereas intratumoral Tcells influence SUV
max
. This may contribute to
the contradictory results between the prognostic role of different PET
parameters, particularly between short and longterm Tcell depleting
chemoimmunotherapeutic regimens. The impact of glucoseuptake in
intratumoral Tcells should be considered when interpreting pre
therapy FDGPET in FL.
The research was funded by: This work was supported by a Hae-
matology Society of Australia and New Zealand and Leukaemia
Foundation PhD scholarship (KN); and the Leukaemia Foundation,
the Mater Foundation and the National Health and Medical Research
Council (MKG). The Translational Research Institute is supported by
the Australian Government.
Keywords: Metabolism, PETCT, Indolent nonHodgkin lymphoma
No conflicts of interests pertinent to the abstract.
SUPPLEMENT ABSTRACTS
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127
FIGURE 1 (A): TMTV in patients with a Tcell
LO
and Tcell
RICH
inflitrative state (Tcell status was defined by a standardized CD4 +CD8A
gene score). (B) TLG in patients with a Tcell
LO
and T
RICH
tumor inflitrate. (C) TMTV in patients with a low vs. high intratumoral FL Bcell
inflitrateb (by flow cytometry) (D) Intratumoral CD8
+
and CD8
+
cell subset specific TCR repertoire clonality according to TMTV status. CD8
+
cells were FACS sorted into activated (PD1
+
LAG3
-ve
), exhausted (PD1
+
LAG3
-ve
) and resting (PD
-ve
LAG3
-ve
subsets. (E) TCR repertoire
clonality in patients with a low vs. high TMTV within TILS sorted into CD4
4
subsets: CXCR5
+
ICOS
+
Tfoilicular helper (T
FH
cells,
CD25
HI
CD127
LO
CXCR5
-ve
regulatory Tcells (T
REG
) and CD4
+
nonT
FH
/T
REG
subsets. (F) Cellular glucose uptake within intratumoral CD19
+
,
CD8
+
and CD4
+
cells. (G) Lymphocyte contribution to overall glucoseuptake after normalizing for % live cells. Avg. cell inflitration : CD19
+
64% CD8
+
4% and CD4
+
18%. (H) Lymphocyte (CD19,CD8A,CD4) gene expression reported according to the prebiopsy ‘lesional
SUX
max
’state
128
-
SUPPLEMENT ABSTRACTS
077 |DIRECTACTING ANTIVIRALS AS PRIMARY TREATMENT
FOR HCVASSOCIATED INDOLENT NONHODGKIN
LYMPHOMAS: THE PROSPECTIVE BART STUDY OF THE
FONDAZIONE ITALIANA LINFOMI
M. Merli
1
, S. Rattotti
2
, M. Spina
3
, F. Re
4
, M. Motta
5
, F. Piazza
6
,
L. Orsucci
7
, Andrés J. M. Ferreri
8
, O. Perbellini
9
, A. Dodero
10
,
D. Vallisa
11
, A. Pulsoni
12
, A. Santoro
13
, V. Zuccaro
14
, E. Chimienti
3
,
F. Russo
4
, C. Visco
15
, A. L. Zignego
16
, L. Marcheselli
17
, S. Luminari
18
,
M. Paulli
19
, R. Bruno
14
, L. Arcaini
20
1
University Hospital “Ospedale di Circolo e Fondazione Macchi” ASST
Sette Laghi, University of Insubria, Hematology, Varese, Italy,
2
Fondazione IRCCS Policlinico San Matteo, Hematology, Pavia, Italy,
3
Centro di Riferimento Oncologico, IRCCS, Medical Oncology and
Immunerelated Tumors, Aviano (PN), Italy,
4
Azienda Ospedaliera Uni-
versitaria, Hematology and BMT Center, Parma, Italy,
5
ASST Spedali
Civili Brescia, Hematology, Brescia, Italy,
6
Azienda Ospedaliera
Universitaria, University of Padova, Medicine, Hematology, Padova,
Italy,
7
Città della Salute e della Scienza di Torino, Hematology, Torino,
Italy,
8
IRCCS San Raffaele Scientific Institute, Lymphoma Unit, Milan,
Italy,
9
San Bortolo Hospital, Hematology Unit, Vicenza, Italy,
10
Fon-
dazione IRCCS Istituto Nazionale dei Tumori, Hematology, Milano, Italy,
11
Ospedale Guglielmo da Saliceto, Hematology, Piacenza, Italy,
12
Sapienza University of Rome, Translational and Precision Medicine,
Roma, Italy,
13
Humanitas Research Hospital, Medical Oncology and
Hematology Unit, Rozzano, Milan, Italy,
14
Fondazione IRCCS Policlinico
San Matteo, University of Pavia, Infectious and Tropical Diseases,
Pavia, Italy,
15
University of Verona, Medicine, Section of Hematology,
Verona, Italy,
16
University of Florence, Clinical and Experimental
Medicine, Interdepartmental Hepatology Center MASVE, Florence, Italy,
17
Fondazione Italiana Linfomi ONLUS, FIL, Modena, Italy,
18
AUSL
IRCCS Reggio Emilia, University of Modena and Reggio Emilia, Hema-
tology, Reggo Emilia, Italy,
19
Fondazione IRCCS Policlinico San Matteo,
University of Pavia, Anatomic Pathology Unit, Pavia, Italy,
20
University
of Pavia, Molecular Medicine, Pavia, Italy
Introduction: The most convincing argument for the role of hepatitis
C virus (HCV) in the pathogenesis of some indolent nonHodgkin
lymphoma (iNHL) subtypes, especially marginalzone lymphomas
(MZL), is represented by retrospective observations of tumor
regression after viral eradication by interferon (IFN)free direct
acting antivirals (DAAs). However, no prospective studies in this
setting have been performed so far.
Methods: In 2016 the Fondazione Italiana Linfomi started the pro-
spective, multicenter, phase 2 BArT study (NCT02836925), evalu-
ating IFNfree DAAs regimens in untreated, HCVRNA+, non
cirrhotic, iNHL patients (pts) without criteria for immediate con-
ventional treatment. Pts with genotypes (GT) 1 and 4 received
ledipasvir (LDV)/sofosbuvir (SOF) for 12 (naïve) or 24 weeks (IFN
experienced), GT 2 pts SOF +ribavirin (RBV) for 12 weeks and GT
3 pts LDV/SOF +RBV for 24 weeks. After amendment (Jul 2017),
GT 2 and 3 pts received the novel SOF/velpatasvir (VEL) regimen
for 12 weeks. The primary objective was sustained virological
response (SVR) while the main secondary objectives were overall
response rate (ORR) of lymphoma, progressionfree survival (PFS)
and toxicity.
Results: Forty pts (17 males, 23 females) were enrolled, including 27
MZL (14 MALT, 9 nodal and 4 splenic), 6 lymphoplasmacytic lym-
phoma (LPL), 4 CD5negative iNHL not otherwise specified (NOS), 2
small lymphocytic lymphoma (SLL) and 1 grade (g) 2 follicular lym-
phoma (FL). Median age was 68 years (yrs) (4583). Stage was III/IV
in 34 pts (85%). Extranodal sites were involved in 14 (40%) and bone
marrow in 23 pts (58%). GT was 1 in 17 (43%), 2 in 21 (52%), 3 in 2
pts (5%). Four pts (10%) previously failed an IFNbased regimen. All
pts received GTappropriate DAAs: 17 LDV/SOF, 8 SOF +RBV, 15
SOF/VEL. The primary endpoint was met as all patients achieved
SVR (100%). DAAs were well tolerated, with 17 pts (43%) experi-
encing 30 g 12 (including 2 RBVrelated g 1 anemia) and 2 g 34
adverse events (g 4 lipase increase; g 3 breast cancer). ORR of
lymphoma was 45%, including 8 pts (20%) achieving complete
response (CR) and 10 (25%) partial response (PR), while 16 (40%)
exhibited stable disease (SD) and 6 (15%) progressed (Tab 1). No
significant difference in ORR was recorded between MZL and non
MZL cases (48 vs 33%, p =0.74). Among MZL, the best ORR was
evidenced in MALT MZL (71%). At a median followup of 33 months
(95% CI 2139) no pt died, 3 additional pts progressed, with a 3yr
PFS of 80% (95% CI 6489%, Fig 1) and 3yr duration of response
for CR/PR pts of 83%.
Conclusions: This is the first prospective trial investigating the role of
DAAs in HCV+iNHL pts not requiring immediate conventional
TABLE 1
Response Histology Total (%)
CD5NOS SLL LPL FL MZL
CR 1 7 8 (20)
PR 1 1 1 1 6 10 (25)
ORR 2 1 1 1 13 18 (45)
SD 1 510 16 (40)
PD 1 1 4 6 (15)
Total 4 2 6 1 27 40
SUPPLEMENT ABSTRACTS
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129
treatment. Our results suggest that HCV eradication with DAAs
should be considered as firstline therapy in this setting.
The research was funded by: Gilead Sciences, Inc
Keywords: Indolent nonHodgkin lymphoma, Therapeutics and Clin-
ical Trials in Lymphoma Other
Conflicts of interests pertinent to the abstract
A. J. M. Ferreri
Consultant or advisory role: Gilead Sciences, Inc
Research funding: Gilead Sciences, Inc
A. Santoro
Consultant or advisory role: Gilead Sciences, Inc
Other remuneration: Gilead Sciences, Inc
R. Bruno
Consultant or advisory role: Gilead Sciences, Inc
L. Arcaini
Consultant or advisory role: Gilead Sciences, Inc
Research funding: Gilead Sciences, Inc
Other remuneration: Gilead Sciences, Inc
078 |PRIMARY EXTRANODAL FOLLICULAR LYMPHOMA IN A
LARGE RETROSPECTIVE SURVEY OF THE INTERNATIONAL
EXTRANODAL LYMPHOMA STUDY GROUP (IELSG31)
A. Conconi
1
, B. Vannata
2
, A. Janikova
3
, A. Ramirez
4
, C. Lobetti
Bodoni
2
, G. Nowakowski
5
, M. Mian
6
, Andrés J. M. Ferreri
7
, G. Ryan
8
,
G. A. Pangalis
9
, M. E. Cabrera
10
, S. Luminari
11
, S. Montoto
12
,
R. Tsang
13
, I. Aurer
14
, C. Visco
15
, L. Mazzucchelli
16
, M. Trneny
17
,
G. Gaidano
18
, M. Federico
19
, A. LopezGuillermo
20
, B. Pro
21
,
E. Zucca
22
1
Azienda sanitaria locale Biella, Ospedale degli Infermi Ematologia,
Biella, Italy,
2
Oncology Institute of Southern Switzerland, Medical
Oncology Clinic, Bellinzona, Switzerland,
3
University Hospital Brno,
Department of Hematology and Oncology, Brno, Czech Republic,
4
Instituto Nacional de Cancerologia, Hematology Department, Mexico
City, Mexico,
5
Mayo Clinic, Division of Hematology, Rochester, Minnesota,
USA,
6
Ospedale di Bolzano, Ematologia e Centro Trapianto Midollo Osseo,
Bolzano, Italy,
7
IRCCS San Raffaele Scientific Institute, Unità Operativa di
Oncologia Medica, Milano, Italy,
8
Peter MacCallum Cancer Institute,
Deptment of Radiation Oncology, Melbourne, Australia,
9
Athens Medical
CenterPsychikon Branch, Hematology Department, Athens, Greece,
10
Hospital del Salvador, Facultad de Medicina, Santiago, Chile,
11
Arcis-
pedale Santa Maria Nuova, Servizio di Ematologia, Reggio Emilia, Italy,
12
St. Bartholomew's Hospital, Department of Medical Oncology, London,
UK,
13
University Health Network, Princess Margaret Hospital, Toronto,
Canada,
14
University Hospital Centre Zagreb, Division of Hematology,
Zagreb, Croatia,
15
University of Verona, Departmento of Medicine
Section of Hematology, Verona, Italy,
16
Istituto Cantonale di Patologia,
EOC, Locarno, Switzerland,
17
Charles University General Hospital Prague,
First Faculty of Medicine, Prague, Czech Republic,
18
Azienda Ospedaliera
“Maggiore della Carità”, Ematologia, Novara, Italy,
19
Università degli Studi
di Modena e Reggio Emilia, Centro Oncologico Modenese, Modena, Italy,
20
Hospital Clínic Universitari, Department of Hematology, Barcelona,
Spain,
21
Northwestern Medicine, Hematology and Medical Oncology,
Chicago, Illinois, USA,
22
Foundation for the Institute of Oncology Research
(IOR), International Extranodal Lymphoma Study Group, Oncology Insti-
tute of Southern Switzerland, Medical Oncology Clinic, Bellinzona,
Switzerland
130
-
SUPPLEMENT ABSTRACTS
Characteristics at diagnosis and clinical course of primary extra-
nodal follicular lymphoma (EFL) was never extensively described.
The International Extranodal Lymphoma Study Group (IELSG) co-
ordinated an international multicenter retrospective survey aimed
to describe the clinical features at diagnosis and outcome of a
population of EFL. A dataset, including 608 pathologically reviewed
cases from 19 different countries was analyzed, their outcome was
compared to the outcome of a population of nodal follicular lym-
phomas. Skin (n =334), gastrointestinal tract (n =72), 22 of whom
with a primary duodenal localization, were the two most frequent
presentation sites. These subsets displayed peculiar features at
diagnosis and significantly different pattern of survival. After me-
dian followup of 5.years, a superior outcome was observed for
primary cutaneous lymphomas [10yr OS:89% (95%CI, 8393%)]
and intermediate outcome for primary gastrointestinal lymphomas
[10yr OS:79% [95%CI, 5990%)] among whom primary duodenal
lymphomas displayed a trend toward the best outcome [10yr
OS:95% (95%CI, 7299%)]. All the other primary extranodal sites
presented an inferior outcome [10yr OS: 59% (95%CI, 4868%)]
analogous to the outcome of primary nodal lymphomas [10yr
OS:57% (95%CI: 4964%)]. These findings support the hypothesis
that some primary lymphoma localizations may represent specific
entities.
Keywords: Extranodal nonHodgkin lymphoma
Conflicts of interests pertinent to the abstract
A. Janikova
Consultant or advisory role: Novartis, Roche, Gilead
Honoraria: Gilead, Roche
079 |PHASE II TRIAL OF RITUXIMAB PLUS CHLORAMBUCIL
FOLLOWED BY A 2YEAR SUBCUTANEOUS RITUXIMAB
MAINTENANCE IN MALT LYMPHOMA PATIENTS (IELSG38)
M. C. Pirosa
1
, L. Orsucci
2
, P. Feugier
3
, M. Tani
4
, Hervé Ghesquieres
5
,
G. Musuraca
6
, L. Baldini
7
, F. Merli
8
, B. De Renzis
9
, E. Gyan
10
,
G. Gini
11
, D. Marino
12
, R. Gressin
13
, F. Morschhauser
14
, F. Palombi
15
,
F. Cavallo
16
, A. Conconi
17
, S. Le Gouill
18
, Hervé Tilly
19
, M. Zanni
20
,
M. G. Cabras
21
, E. Capochiani
22
, C. Califano
23
, A. L. Molinari
24
,
A. Pulsoni
25
, F. Angrilli
26
, G. Cartron
27
, O. Casasnovas
28
, L. Devizzi
29
,
C. Haioun
30
, R. Houot
31
, A. M. Liberati
32
, U. Occhini
33
, M. Merli
34
,
G. Pietrantuono
35
, F. Re
36
, M. Spina
37
, F. Esposito
38
, F. Bertoni
39
,
D. Rossi
39
, N. Ielmini
38
, S. Luminari
8
, F. Cavalli
38
, E. Zucca
40
,
A. Stathis
41
, C. Thieblemont
42
1
Oncology Institute of Southern Switzerland, Hematology, Bellinzona,
Switzerland,
2
A.O.U. Città della Salute e della Scienza di Torino,
Dipartimento di Oncologia ed Ematologia, Torino, Italy,
3
CHU Nancy
Brabois, Hématologie, Nancy, France,
4
Ospedale Santa Maria delle
Croci, Dipartimento di Oncologia ed Ematologia, Ravenna, Italy,
5
Centre Hospitalier Universitaire de Lyon, Hôpital Lyon Sud Héma-
tologie, PierreBénite, France,
6
IRCCS Istituto Romagnolo per lo Studio
dei Tumori "Dino Amadori" IRST S.r.l., Ematologia, Meldola, Italy,
7
Fondazione IRCCS Granda, Ospedale Maggiore Policlinico Ema-
tologia, Milano, Italy,
8
Arcispedale Santa Maria Nuova, Servizio di
Ematologia, Reggio Emilia, Italy,
9
CHU Estaing, Service d’Hématologie
Clinique, ClermontFerrant, France,
10
CHU de Tours, Service d’héma-
tologie, Tours, France,
11
AU Ospedali Riuniti Ancona, Clinica di Ema-
tologia, Ancona, Italy,
12
Istituto Oncologico Veneto IRCCS, UOC
Oncologia 1, Padova, Italy,
13
CHU Crenoble Alpes, Service Hématologie,
Grenoble, France,
14
CHU de Lille Hôpital Claude Huriez, Service des
SUPPLEMENT ABSTRACTS
-
131